Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:12]=1)[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]>C(O)(=O)C>[CH2:9]([O:8][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:12]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)CCCC(=O)c1cn(-c2cccnc2)c2ccccc12
Solvent: CC(=O)O
Product: CCOC(=O)CCCCc1cn(-c2cccnc2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5 g of 3-(1-oxo-4-ethoxycarbonylbutyl)-N-(3-pyridyl)indole in 75 ml of glacial acetic acid is added 5 g of borane-tert-butylamine complex. The reaction mixture is stirred at room temperature overnight. The reaction mixture is concentrated, water is added to the residue and the product is extracted with methylene chloride. The organic layer is separated, washed first with concentrated sodium carbonate solution, then with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness to yield 3-(4-ethoxycarbonylbutyl)-N-(3-pyridyl)-indole, melting at 56°-58°.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[CH:21](=O)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(O)(=O)C.[BH4-].[Na+]>CN(C=O)C>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: CCCCCCC=O
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCCCCCCNc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 18 h
Yield: 41.1 %

Procedure:
A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.1 g, 4.0 mmol) and heptanal (3.4 mL, 24 mmol) and acetic acid (2 mL) in DMF (20 mL) was heated until all solid was dissolved. To the mixture was added sodium borohydride (605 mg, 16 mmol) and kept at room temperature for 18 h. To the mixture was added sodium borohydride (150 mg, 3.9 mmol) and kept at room temperature for 1 d. The mixture was extracted with ethyl acetate (200 mL) and water (100 mL). The organic layer was washed with water (100 mL). The solvent was removed in vacuo to give an oil. The oil was purified by column chromatography (Silca Gel, 33% EtOAc:CH2Cl2) to give 2-(2,6-Dioxo-piperidin-3-yl)-4-heptylamino-isoindole-1,3-dione as a yellow solid (610 mg, 41% yield): mp, 107-109° C.; 1H NMR (DMSO-d6) δ 0.82-0.87 (m, 3H, CH3), 1.24-1.29 (m, 8H, 4 CH2), 2.00-2.04 (m, 1H, CHH), 2.43-2.62 (m, 2H, CH2), 2.82-2.96 (m, 1H, CHH), 3.23-3.31 (m, 2H, CH2), 5.06 (dd, J=5.3, 12.4 Hz, 1H, NCH), 6.51 (t, J=5.9 Hz, 1H, NH), 7.01 (d, J=7.0 Hz, 1H, Ar), 7.07 (d, J=8.6 Hz, 1H, Ar), 7.57 (dd, J=7.4, 8.4 Hz, 1H, Ar), 11.10 (s, 1H, NH); 13C NMR (DMSO-d6) δ 13.91, 22.03, 22.17, 26.28, 28.42, 28.69, 30.98, 31.22, 34.84, 48.55, 109.03, 110.36, 117.13, 132.18, 136.24, 146.43, 167.29, 168.96, 170.05, 172.77; Anal Calcd for C20H25N3O4: C, 64.67; H, 6.78; N, 11.31. Found: C, 64.62; H, 6.76; N, 11.13.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([N+:13]([O-])=O)[CH:10]=[CH:11][CH:12]=2)=[CH:4][C:3]=1[CH2:18][CH3:19].O>C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=2)[NH2:13])=[CH:4][C:3]=1[CH2:18][CH3:19]
Reactant: CCc1cc(Oc2cccc([N+](=O)[O-])c2)ccc1Cl
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CCc1cc(Oc2cccc(N)c2)ccc1Cl
Yield: 112.1 %

Procedure:
EX-8B) To a solution of 3-(4-chloro-3-ethylphenoxy)-1-nitrobenzene (10 g, 0.036 mol) from EX-A in 400 mL of glacial acetic acid and 1 mL of water was added zinc metal (20 g, 0.305 mol) at room temperature, and the resultant mixture was stirred for 1 h. The reaction mixture was filtered through celite. The filtrate was neutralized with ammonium hydroxide and extracted with diethyl ether. The organic layer was washed with water and brine, dried over MgSO4, and concentrated in vacuo to give 10 g (100%) of the desired 3-(4-chloro-3-ethylphenoxy)aniline product as a dark orange oil, which was greater than 90% pure by reverse phase HPLC analysis. HRMS calcd. for C14H14ClNO: 248.0842 [M+H]+, found: 248.0833.
Reaction SMILES: [CH:1]([B-](F)(F)F)=[CH2:2].[K+].O1CCOCC1.Br[C:15]1[N:16]=[C:17]([C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[S:18][C:19]=1[C:20]1[N:24]=[CH:23][N:22]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[N:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.CCOC(C)=O.O>[CH3:30][Si:29]([CH3:32])([CH3:31])[CH2:28][CH2:27][O:26][CH2:25][N:22]1[CH:23]=[N:24][C:20]([C:19]2[S:18][C:17]([C:33]3[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=3)=[N:16][C:15]=2[CH:1]=[CH2:2])=[N:21]1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2sc(-c3ccncc3)nc2Br)n1
Reactant: C=C[B-](F)(F)F
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: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1nc(-c2ccncc2)sc1-c1ncn(COCC[Si](C)(C)C)n1
Temperature: 110 °C
Reaction time: 8 h
Yield: 75.6 %

Procedure:
Into a sealed tube was added potassium vinyltrifluoroborate (1.34 g, 10.0 mmol), 1,4-dioxane (21.0 mL, 269 mmol), 4-[4-bromo-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]pyridine (2.0 g, 4.6 mmol) and 2 M sodium carbonate in water (9.10 mL, 18.2 mmol). The reaction was degassed with nitrogen for 15 min then tetrakis(triphenylphosphine)palladium(0) (527 mg, 0.456 mmol) was added. The tube was sealed and the reaction was heated in an oil bath at 110° C. with stirring overnight. The reaction solution was cooled to room temperature, water (10 mL) and EtOAc (10 mL) were added, and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (SiO2, elution with 0-10% MeOH in DCM) to give the title compound as a yellow solid (1.34 g 81%). LCMS: (FA) ES+ , 386. 1H NMR (400 MHz, d6-DMSO) δ: 8.92 (s, 1H), δ 8.74-8.76 (dd, J=1.75 Hz, J=1.5 Hz 2H), 7.96-7.98 (dd, J=1.75 Hz, 2H), 6.34-6.40 (dd, J=2.3 Hz, 12H), 5.62-5.65 (dd, J=2.3 Hz, 1H), 5.60 (s, br, 2H), 3.63-3.68 (m, 2H), 0.86-0.90 (m, 2H), −0.04 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]2[N:25]=[CH:26][CH:27]=[C:4]2[N:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH2:43][CH:42]3[N:44]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH:38]([CH2:39][O:40][CH2:41]3)[CH:37]=2)O1.B(O)O.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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].C(OCC)(=O)C.O>[CH3:14][Si:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:10][CH2:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]1[N:5]2[N:25]=[CH:26][CH:27]=[C:4]2[N:3]=[C:2]([C:36]2[CH2:37][CH:38]3[N:44]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH:42]([CH2:41][O:40][CH2:39]3)[CH:43]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C2C=C(B3OC(C)(C)C(C)(C)O3)CC1COC2
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2ccnn12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1C2C=C(c3cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n4nccc4n3)CC1COC2
Yield: 87.5 %

Procedure:
A solution of 5-chloro-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (1.01 g, 2.35 mmol) in DME (18 mL) was treated with boronate tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-oxa-9-azabicyclo[3.3.1]non-6-ene-9-carboxylate (910 mg, 2.59 mmol), Pd(dppf)Cl2.CH2Cl2 (191 mg, 0.24 mmol), 2M aqueous Na2CO3 (9.1 mL) under argon and heated at 100° C. for 16 h. Upon cooling, water (50 mL) and ethyl acetate (70 mL) was added. Two layers were separated and organic layer was collected. Aqueous layer was then extracted with ethyl acetate (2×70 mL). Combined organic layer was washed with brine (1×150 mL), dried (Na2SO4) and evaporated under reduced pressure to give crude material which was purified by column chromatography (0-40% hexane-ethyl acetate) to provide the desired product tert-butyl 7-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)-3-oxa-9-azabicyclo[3.3.1]non-6-ene-9-carboxylate (1.27 g). HPLC-MS tR=3.09 min (UV254 nm). Mass calculated for formula C30H51N5O5Si2 617.3; observed MH+ (LCMS) 618.2 (m/z).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[N:17]=[C:16]([C:18](=S)[NH2:19])[CH:15]=[CH:14][CH:13]=3)[CH:9]=[N:8]2)[CH:2]=1.[CH3:21][N:22]([CH:24]=O)[NH2:23]>>[CH3:24][N:22]1[CH:21]=[N:19][C:18]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([C:10]3[CH:9]=[N:8][N:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:11]=3)[N:17]=2)=[N:23]1
Reactant: NC(=S)c1cccc(-c2cnn(-c3cccnc3)c2)n1
Reactant: CN(N)C=O
Product: Cn1cnc(-c2cccc(-c3cnn(-c4cccnc4)c3)n2)n1

Procedure:
0.57 g (2 mmol) of 6-(l-pyridin-3-yl-1H-pyrazol-4-yl)pyridine-2-carbothioamide and 2.5 ml (27 mmol) of 1-methyl-1-formylhydrazine were stirred at 145° C. for 6 h. After cooling, the mixture was purified by chromatography on silica gel (cyclohexane/acetone).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C@@H:4]([CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])[C@@H:3]1[C:10](O)=[O:11].S(Cl)([Cl:16])=O>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:13])[C@@H:4]([CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])[C@@H:3]1[C:10]([Cl:16])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)[C@@H](CC(Cl)(Cl)Cl)[C@@H]1C(=O)O
Solvent: c1ccccc1
Product: CC1(C)[C@@H](CC(Cl)(Cl)Cl)[C@@H]1C(=O)Cl
Yield: 77 %

Procedure:
Into 50 ml of water were dissolved 11.0 g of sodium hydroxide, followed by the addition of 50.0 g of ethyl cis, trans-2,2-dimethyl-3-(2,2,2-trichloroethyl) cyclopropanecarboxylate and about 100 ml of ethanol as a solvent. This mixture was stirred at room temperature for one day. To the reaction mixture was further added a solution of 8.0 g sodium hydroxide in 15 ml of water and the mixture was stirred at room temperature for two days. The resultant reaction mixture was distilled under reduced pressure to remove ethanol and extracted with diethyl ether to recover the unreacted ethyl cis, trans-2,2-dimethyl-3-(2,2,2-trichloroethyl) cyclopropanecarboxylate. Then, the alkaline aqueous layer was acidified by the addition of hydrochloric acid and extracted with diethyl ether. The etheral layer was dried over anhydrous magnesium sulfate and distilled to remove diethyl ether. By the above procedure there were obtained 45.2 g of cis, trans-2,2-dimethyl-3-(2,2,2-trichloroethyl) cyclopropanecarboxylic acid. To 45.2 g of the carboxylic acid were added 131 g of thionyl chloride and 150 g of benzene and the mixture was heated under reflux overnight. The reaction mixture was then distilled under reduced pressure to remove the low-boiling fraction. The resultant residue was purified by distillation under reduced pressure to obtain 37.2 g of cis, trans-2,2-dimethyl-3-(2,2,2-trichloroethyl) cyclopropanecarboxylic acid chloride which displayed the following NMR spectrum [yield 77% based on the ethyl cis, trans-2,2-dimethyl-3-(2,2,2-trichloroethyl) cyclopropanecarboxylate].
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Cl:6][C:7]1[CH:8]=[C:9]([S:21](Cl)(=[O:23])=[O:22])[CH:10]=[CH:11][C:12]=1[NH:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15]>O1CCCC1>[C:1]([NH:5][S:21]([C:9]1[CH:10]=[CH:11][C:12]([NH:13][S:14]([C:17]([F:20])([F:18])[F:19])(=[O:16])=[O:15])=[C:7]([Cl:6])[CH:8]=1)(=[O:23])=[O:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccc(NS(=O)(=O)C(F)(F)F)c(Cl)c1
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1ccc(NS(=O)(=O)C(F)(F)F)c(Cl)c1
Reaction time: 8 h
Yield: 62.3 %

Procedure:
A solution of t-butylamine (0.6 g) and 3-chloro-4-(trifluoromethanesulfonamido)benzenesulfonyl chloride (1.5 g) in tetrahydrofuran (20 ml) was allowed to stand overnight. The resultant mixture was concentrated and shaken with chloroform and 5% aqueous hydrochloric acid. The chloroform extract was concentrated and recrystallized from toluene to give 1.03 g of N-t-butyl-3-chloro-4-(trifluoromethanesulfonamido)benzenesulfonamide. M.P., 123°-127.5° C.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:24](=[O:25])[N:11]3[N:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)=[C:15](Cl)[C:10]3=[N:9]2)=[CH:5][CH:4]=1.[C-:30]#[N:31].[K+]>CN1CCCC1=O>[F:29][C:2]([F:28])([F:1])[C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:24](=[O:25])[N:11]3[N:12]=[CH:13][C:14]([C:17]4[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=4)=[C:15]([C:30]#[N:31])[C:10]3=[N:9]2)=[CH:5][CH:4]=1
Reactant: [C-]#N
Reactant: O=c1n(Cc2ccc(C(F)(F)F)cc2)nc2c(Cl)c(-c3ccc(Cl)cc3)cnn12
Agent: [K+]
Solvent: CN1CCCC1=O
Product: N#Cc1c(-c2ccc(Cl)cc2)cnn2c(=O)n(Cc3ccc(C(F)(F)F)cc3)nc12
Temperature: 120 °C
Yield: 72.1 %

Procedure:
A suspension of 2-(4-(trifluoromethyl)benzyl)-8-chloro-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (43.8 mg, 0.10 mmol), prepared as described in example 361G, and KCN (33 mg, 0.5 mmol) in dry 1-methyl-2-pyrrolidinone (1 mL) was heated at 120° C. for 2 h under argon. HPLC/MS analysis indicated complete reaction. The reaction mixture was concentrated under vacuum with co-evaporation of toluene (5 mL×2) to obtain a yellow solid. The crude product was purified by reversed phase preparative HPLC (C-18, MeOH/H2O gradient, 0.1% TFA) to obtain title compound (31 mg, 72%), 2-(4-(trifluoromethyl)benzyl)-7-(4-chlorophenyl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-b]pyridazine-8-carbonitrile as a yellow solid. MS [M+H]+ 430; HPLC retention time=3.76 min.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[CH3:30][C:31]1([OH:39])[CH2:34][N:33]([CH:35]2[CH2:38][NH:37][CH2:36]2)[CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:37]4[CH2:38][CH:35]([N:33]5[CH2:34][C:31]([CH3:30])([OH:39])[CH2:32]5)[CH2:36]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: CC1(O)CN(C2CNC2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CC(C)(O)C4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.3 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.092 g, 0.234 mmol), 3-methyl-[1,3′]biazetidinyl-3-ol (0.040 g, 0.28 mmol) and 4 Å molecular sieves (0.25 g) in DCE (3 mL). The reaction mixture was stirred for 90 min at room temperature. Sodium triacetoxyborohydride (0.099 g, 0.47 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 10:90) to give 587 as a white solid (0.107 g, 89%). LCMS (Method I): RT=2.33 min, [M+H]+ 518.2 1H NMR (300 MHz, DMSO-d6): δ 8.03-7.99 (m, 1 H), 7.65-7.61 (m, 1 H), 7.27-7.22 (m, 2 H), 4.49-3.95 (m, 4 H), 3.84 (s, 2 H), 3.80-3.74 (m, 4 H), 3.36-3.31 (s, 3 H), 3.31-3.20 (m, 6 H), 3.11-3.01 (m, 4 H), 2.98-2.93 (m, 2 H), 1.34 (m, 5 H)
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([CH:30]4[CH2:33][O:32][CH2:31]4)[CH2:26][C@H:25]3[CH3:34])=[CH:20][N:19]=2)[C:3]1=[O:35].Br[C:37]1[CH:44]=[C:43]([F:45])[CH:42]=[C:41]([N:46]2[N:55]=[CH:54][C:53]3[C:48](=[C:49]([F:60])[CH:50]=[C:51]([C:56]([CH3:59])([CH3:58])[CH3:57])[CH:52]=3)[C:47]2=[O:61])[C:38]=1[CH:39]=[O:40].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC([O-])=O.[Na+]>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].O.CC#N>[C:56]([C:51]1[CH:52]=[C:53]2[C:48](=[C:49]([F:60])[CH:50]=1)[C:47](=[O:61])[N:46]([C:41]1[CH:42]=[C:43]([F:45])[CH:44]=[C:37]([C:6]3[CH:5]=[C:4]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH2:29][CH2:28][N:27]([CH:30]6[CH2:31][O:32][CH2:33]6)[CH2:26][C@H:25]5[CH3:34])=[CH:20][N:19]=4)[C:3](=[O:35])[N:2]([CH3:1])[CH:7]=3)[C:38]=1[CH:39]=[O:40])[N:55]=[CH:54]2)([CH3:59])([CH3:57])[CH3:58]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cc(F)cc(Br)c3C=O)ncc2c1
Reactant: C[C@@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: C[C@@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3C=O)cn(C)c2=O)nc1
Temperature: 80 °C
Yield: 30.7 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with (R)-1-methyl-3-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (173 mg, 1.0 eq., 0.36 mmol), 2-bromo-6-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-fluorobenzaldehyde 101i (152 mg, 1.0 eq., 0.36 mmol), K3PO4 (152 mg, 2.0 eq., 0.72 mmol), PdCl2(dppf) (26 mg, 0.1 eq., 0.036 mmol), NaOAc (59 mg, 2.0 eq., 0.72 mmol), CH3CN (20 mL), and H2O (0.8 mL). After three cycles of vacuum/argon flush, the mixture was heated at 80° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 40:1 DCM/EtOH to afford 107a as yellow solid (77 mg, 31%). MS: [M+H]+ 696.3.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][O:5][CH3:6].Cl[CH2:8][C:9]1[N:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[O:24][CH3:25])[S:11][N:10]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[CH3:25][O:24][C:17]1[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:16]=1[CH2:15][NH:14][C:12]1[S:11][N:10]=[C:9]([CH2:8][N:2]([CH2:3][CH2:4][O:5][CH3:6])[CH3:1])[N:13]=1
Reactant: COc1ccc(CNc2nc(CCl)ns2)c(OC)c1
Reactant: CNCCOC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COCCN(C)Cc1nsc(NCc2ccc(OC)cc2OC)n1
Temperature: 25 °C

Procedure:
10 mmol of N-methyl-2-methoxyethylamine is added to the solution of (3-Chloromethyl-[1,2,4]thiadiazol-5-yl)-(2,4-dimethoxy-benzyl)-amine (Intermediate XXVIII) in 50 ml THF and 10 mmol of Cs2CO3 is added. The reaction is heated at reflux overnight. The reaction is cooled to room temperature and filtered, washed with THF. The filtrate is concentrated and purified by RP-HPLC.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=1)[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24])=[O:17].C(N(CC)CC)C.ClC(OCC)=O.[NH2:42][OH:43]>[Cl-].[Na+].O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=1)[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:42][OH:43])=[O:24])=[O:17]
Reactant: O=C(O)CCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1
Reactant: NO
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1)NO
Temperature: 0 °C
Reaction time: 2 h
Yield: 46.8 %

Procedure:
5-(3-((5-fluoro-2-oxoindolin-3-ylidene)methyl)benzamido)pentanoic acid (382 mg, 1 mmol), triethylamine (151 mg, 1.5 mmol) and 20 ml of DMF were stirred at 0° C. while ethyl chloroformate (163 mg, 1.5 mmol) was added. The mixture was stirred at 0° C. for 2 hours, and then 50% aqueous solution of hydroxylamine (1.32 g, 20 mmol) was added. The mixture was stirred for 3 hours at room temperature, and then diluted with 1000 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (186 mg, 47%) as a brown solid. LC-MS (m/z) 398 (M+1).
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:22])[C@@H:15]([CH2:20][OH:21])[CH2:16][CH:17]([CH3:19])[CH3:18])C1C=CC=CC=1.C1C[O:26]CC1.OO.O.[OH-].[Li+].[OH-].[K+].S([O-])([O-])=O.[Na+].[Na+]>O.C(Cl)(Cl)Cl>[OH:21][CH2:20][C@@H:15]([CH2:16][CH:17]([CH3:18])[CH3:19])[C:14]([OH:22])=[O:26]
Reactant: C1CCOC1
Reactant: CC(C)C[C@H](CO)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: O=S([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)C[C@H](CO)C(=O)O
Temperature: 0 °C
Yield: 90.5 %

Procedure:
Intermediate (2b) (13.9 g, 40.8 mmol) was dissolved in THF (200 mL, 2 mol) and stirred at 0° C. 9 M hydrogen peroxide in water (46.3 mL) was added, followed by dropwise addition of 1.5 M lithium hydroxide monohydrate in water (54.4 mL). The mixture was then warmed to room temperature and stirred for 2.5 hours. Potassium hydroxide (4.6 g, 81.6 mmol) was added and the mixture was heated at 60° C. for 30 minutes and then cooled at room temperature. To this was added a solution of sodium sulfite (10 g in 200 mL water) followed by water and chloroform (200 mL of each). The aqueous layer was extracted twice more with CHCl3 (150 mL), acidified and extracted with EtOAc. The organic layer was then washed with saturated aqueous NaCl, dried over MgSO4, filtered, and rotovaped to provide intermediate (2c) (5.4 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH2:27](O)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:27]([O:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1)=[O:3])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCO
Reactant: CCCCCCCCc1ccc2nc(-c3ccc(C(=O)O)cc3)sc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCOC(=O)c1ccc(-c2nc3ccc(CCCCCCCC)cc3s2)cc1
Temperature: 25 °C
Yield: 51.1 %

Procedure:
To 0.30 g (0.82 mM) of 2-(p-carboxyphenyl)-6-octylbenzothiazole, 0.12 g (0.92 mM) of octanol and 10 ml of methylene chloride were added, followed by addition of 0.17 g (0.82 mM) of N,N'-dicyclohexylcarbodiimide (DCC) and 0.02 g of 4-dimethylamino pyridine under stirring at room temperature and further stirring for 6 hours at room temperature. After the reaction, the resultant N,N'-dicyclohexylurea was recovered by filtration, followed by washing with methylene chloride to be added to the filtrate. The solvent of the resultant filtrate was distilled-off under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (eluent: toluene), followed by recrystallization from a mixture solvent of toluene/methanol to obtain 0.20 g of 2-(p-octyloxycarbonylphenyl)-6-octylbenzothiazole (Yield: 51.1%). ##STR196##
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])[C:11]([N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(OCC)C>[CH2:27]([NH:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])[C:11]([N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Nc1ccc(NC(=O)C(=O)N2CCC(Cc3ccccc3)CC2)cc1
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: O=C(Nc1ccc(NCc2ccccc2)cc1)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from N-(4-amino-phenyl)-2-(4-benzyl-piperidin-1-yl)-2-oxo-acetamide hydrochloride (Example 73) and benzaldehyde (Aldrich) according to the method described in Example 91. Melting Point: 126-128° C. (diethylether)