Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].B(F)(F)F.CCOCC.[CH2:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[Cl-].[Na+]>>[CH2:18]([C:5]1[CH:6]=[CH:7][CH:8]=[C:1]([OH:2])[C:3]=1[OH:4])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: C=CCCCCCCC
Reactant: Oc1ccccc1O
Agent: FB(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Product: CCCCCCCCCc1cccc(O)c1O
Temperature: 104 °C

Procedure:
Into a 500ml, 3-neck reaction vessel was placed 64.8g (0.3125 moles) of catechol, after which time it was heated to 104° C. under a nitrogen flow. After the catechol was completely melted, 3.25g (5% based on the wt. of the catechol) of borontrifluoride-etherate was added dropwise, with stirring. After adding all of the catalyst, 63.2 g (0.25 moles) of 1-nonene was added dropwise to the reaction mixture, the rate of addition being adjusted so as to maintain a temperature of 130° C. After all of the 1-nonene was added, the resultant mixture was allowed to react for 3 hours, after which time 100 ml of a 10% sodium chloride solution was added to the reaction mixture. The resultant mixture was then stirred for 15 minutes at 95° to 100° C., after which time the bottom layer was separated. The mixture was again stirred at 95° to 100° C. for 15 minutes, after which time the bottom layer was again separated. The organic layer was then isolated to obtain a viscous, brown oil of the formula ##STR7##
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@@H:8]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:27])[NH:17][C:18]1[N:19]=[C:20]2[N:24]([CH:25]=1)[CH:23]=[C:22](Br)[S:21]2)=[O:10])([CH3:4])([CH3:3])[CH3:2].[C:35]([NH:42][C:43]1[CH:48]=[CH:47][C:46](B2OC(C)(C)C(C)(C)O2)=[CH:45][CH:44]=1)([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>>[C:38]([O:37][C:35](=[O:36])[NH:42][C:43]1[CH:44]=[CH:45][C:46]([C:22]2[S:21][C:20]3=[N:19][C:18]([NH:17][C:16]([C@@H:12]4[CH2:13][CH2:14][CH2:15][N:11]4[C:9](=[O:10])[C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:34])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:27])=[CH:25][N:24]3[CH:23]=2)=[CH:47][CH:48]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1cn2cc(Br)sc2n1)c1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cn3cc(NC(=O)[C@@H]4CCCN4C(=O)[C@@H](NC(=O)OC(C)(C)C)c4ccccc4)nc3s2)cc1
Yield: 5 %

Procedure:
Compound A37 was synthesized from compound 23 (0.100 mmol) and 4-(Boc-amino)benzeneboronic acid pinacol ester (0.150 mmol), following the procedure as described for compound A1, as a white lyophilized powder in 5% yield. MS (ESI, EI+) m/z=661.27 (MH+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([O:18][CH:19]([CH3:23])[CH2:20][NH:21][CH3:22])=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:37][O:38][C:39](=[O:44])[CH2:40][CH2:41][CH2:42]Br>ClCCl>[CH3:37][O:38][C:39](=[O:44])[CH2:40][CH2:41][CH2:42][N:21]([CH2:20][CH:19]([O:18][C:16]1[C:17]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[C:10]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:11][C:12]=2[N:13]=[CH:14][N:15]=1)[CH3:23])[CH3:22]
Reactant: COC(=O)CCCBr
Reactant: CNCC(C)Oc1ncnc2oc(-c3ccccc3)c(-c3ccc(OC)cc3)c12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCCN(C)CC(C)Oc1ncnc2oc(-c3ccccc3)c(-c3ccc(OC)cc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
Put 25 mg (0.064 mmol) (+/−)-2-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}-N-methylpropane-1-amine with 13 mg (0.128 mmol) triethylamine in 250 μl dichloromethane. Add 23.2 mg (0.128 mmol) 4-bromobutyric acid methyl ester and stir overnight at RT. Add the same amounts of triethylamine and 4-bromobutyric acid methyl ester again and stir for a further 24 h at RT. Then concentrate by evaporation and purify the residue by thick-layer chromatography on silica gel (solvent: dichloromethane/methanol 95:5). Extract the product-containing zone with dichloromethane/methanol 9:1. 22.4 mg of the target compound is obtained as raw product.
Reaction SMILES: Cl.[C:2]1([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[S:13][CH:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]([F:37])([F:36])[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=1[C:33](Cl)=[O:34]>>[F:21][C:22]([F:36])([F:37])[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][C:24]=1[C:33]([N:18]1[CH2:19][CH2:20][CH:15]([C:12]2[S:13][CH:14]=[C:10]([CH2:9][CH2:8][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:11]=2)[CH2:16][CH2:17]1)=[O:34]
Reactant: c1ccc(CCc2csc(C3CCNCC3)n2)cc1
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1C(F)(F)F
Agent: Cl
Product: O=C(c1cc(C(F)(F)F)ccc1C(F)(F)F)N1CCC(c2nc(CCc3ccccc3)cs2)CC1

Procedure:
4-[4-(2-Phenylethyl)-1,3-thiazol-2-yl]piperidine hydrochloride (II-1, 309 mg) is reacted analogously to Example I-63 with 2,5-bis(trifluoromethyl)benzenecarbonyl chloride (304 mg). After chromatographic purification, this gives [2,5-bis(trifluoromethyl)phenyl]{4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidin-1-yl}methanone (282 mg).
Reaction SMILES: [Li]CCCC.Br[C:7]1[C:15]2[C:14]([Cl:16])=[N:13][CH:12]=[N:11][C:10]=2[N:9]([CH:17]([CH3:19])[CH3:18])[CH:8]=1.[C:20](=[N:33][C:34]1[CH:35]=[C:36]([CH:43]=[C:44]([O:46][CH3:47])[N:45]=1)[C:37](N(OC)C)=[O:38])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCOCC>[C:20](=[N:33][C:34]1[CH:35]=[C:36]([C:37]([C:7]2[C:15]3[C:14]([Cl:16])=[N:13][CH:12]=[N:11][C:10]=3[N:9]([CH:17]([CH3:19])[CH3:18])[CH:8]=2)=[O:38])[CH:43]=[C:44]([O:46][CH3:47])[N:45]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cc(C(=O)N(C)OC)cc(N=C(c2ccccc2)c2ccccc2)n1
Reactant: CC(C)n1cc(Br)c2c(Cl)ncnc21
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1cc(C(=O)c2cn(C(C)C)c3ncnc(Cl)c23)cc(N=C(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
n-BuLi (9.40 mL, 2.5 M in Hexane, 23.3 mmol) was added dropwise to a solution of 5-Bromo-4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (6.25 g, 22.2 mmol) in Et2O (190 mL) at −78° C. and stirred for 1 h. 2-(Benzhydrylidene-amino)-6,N-dimethoxy-N-methyl-isonicotinamide (10.0 g, 26.6 mmol) was added to the reaction mixture slowly and stirred for 3h, warmed to room temperature, and quenched with saturated aqueous NH4Cl (200 mL). The aqueous layer was extracted with EtOAc (3×200 mL) and the combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to provide a crude solid. Purification by flash column chromatography (ethyl acetate/hexanes 1:1) afforded the title compound as a yellow solid (7.31 mg, 63%). MS: 511.3 (MH+); HPLC Rf: 3.1 min. (HPLC method 3); HPLC purity: 100%.
Reaction SMILES: [CH2:1]([N:5]([CH2:39][CH2:40][CH2:41][CH3:42])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=O)=[CH:16][CH:15]=2)=[C:8]([O:21][Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:43]([C:45]1[C:46](=[C:53]([C:56]#[N:57])[C:54]#[N:55])[O:47][C:48]([CH3:52])([CH3:51])[C:49]=1[CH3:50])#[N:44].C([O-])(=O)C.[NH4+]>C(O)C.O1CCCC1>[CH2:39]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=[CH:50][C:49]3[C:48]([CH3:51])([CH3:52])[O:47][C:46](=[C:53]([C:54]#[N:55])[C:56]#[N:57])[C:45]=3[C:43]#[N:44])=[CH:16][CH:15]=2)=[C:8]([O:21][Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:7]=1)[CH2:40][CH2:41][CH3:42]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C)s2)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 47 h
Yield: 56.5 %

Procedure:
In 12 ml of ethanol and 4 ml of tetrahydrofuran were dissolved 500 mg (0.84 mmol) of 5-[2-[4-dibutylamino-2-(tert-butyldiphenylsiloxy)phenyl]vinyl]thiophene-2-carboaldehyde and 185 mg (0.93 mmol) of 2-(3-cyano-4,5,5-trimethyl-2(5H)-furanylidene)propanedinitrile. To this mixture was added 65 mg of ammonium acetate, and the mixture was stirred at room temperature for 47 hours. The solvent was evaporated off and the residue was washed with ethanol. The residue was purified by silica gel column chromatography and washed with ethanol to give 369 mg of a dark greenish brown crystal (yield: 56.6%; mp: 218-219° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[C:3]=1[SH:12].[CH3:13]O>S(=O)(=O)(O)O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:13])=[O:7])=[C:4]([CH3:11])[C:3]=1[SH:12]
Reactant: Cc1c(C(=O)O)ccc(Cl)c1S
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc(Cl)c(S)c1C

Procedure:
Under an atmosphere of nitrogen, 3.60 g (17.8 mmol) of 4-chloro-3-mercapto-2-methylbenzoic acid in 50 ml of absolute methanol and 1 ml of concentrated sulfuric acid were heated under reflux for 17 h. The mixture was freed from solvent, and the residue was taken up in water. After two extractions with ethyl acetate, the combined organic phases were dried, filtered under an atmosphere of nitrogen and freed from the solvent. What was isolated were 3.2 g of pure product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH:8][C:9](=O)[CH3:10].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[CH3:10][C:9]1[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[CH2:6][CH2:7][N:8]=1
Reactant: CC(=O)NCCc1cccs1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1=NCCc2sccc21

Procedure:
In close analogy to the procedure described above, N-(2-Thiophen-2-yl-ethyl)-acetamide is reacted with phosphorus pentoxide to provide the title compound.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[C:4]([S:32]CC2C=CC(OC)=CC=2)=[C:5]([C:9]([CH2:28][CH:29]([CH3:31])[CH3:30])([CH3:27])[C:10]([NH:12][C@H:13]([C:23]([NH:25][CH3:26])=[O:24])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[F:42][C:2]([F:1])([F:43])[C:3]1[C:4]([SH:32])=[C:5]([C:9]([CH2:28][CH:29]([CH3:31])[CH3:30])([CH3:27])[C:10]([NH:12][C@H:13]([C:23]([NH:25][CH3:26])=[O:24])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(C)(CC(C)C)c1cccc(C(F)(F)F)c1SCc1ccc(OC)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(C)(CC(C)C)c1cccc(C(F)(F)F)c1S
Temperature: 0 °C

Procedure:
An ice-cooled solution of 3-trifluoromethyl-2-(4-methoxybenzylthio)-N-[2-(4-methoxyphenyl)-1-(S)-(methylaminocarbonyl)ethyl]-α-(2-methylpropyl)phenylpropanamide (D13) (308 mg, 0.5 mmol) and anisole (0.1 ml) in trifluoroacetic acid (5 ml) was treated with mercuric acetate (160 mg, 0.5 mmol). After 15 min the solvent was evaporated and the residue was azeotroped dry with toluene. The residual oil was triturated with ether to give a white solid, which was separated and washed with a little ether. The solid was dissolved in dry DMF (3 ml) and the solution was purged with nitrogen. Hydrogen sulphide gas was bubbled through the solution for 3 min. The resulting black suspension was purged with nitrogen for 30 min, then the solvent was evaporated in vacuo. Column chromatography (10 g silica) eluting with ethyl acetate and trituration of the product with pentane gave the title compound as a 1:1 mixture of diastereoisomers (88 mg, 35%), mp 88°-102° C.
Reaction SMILES: [ClH:1].Cl.[C:3]1([C:9]2[O:13][N:12]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:10]=2)[CH:8]=[CH:7]C=[CH:5][CH:4]=1.C(O)(=O)C1C=C[N:24]=CC=1>>[ClH:1].[ClH:1].[N:24]1[CH:7]=[CH:8][C:3]([C:9]2[O:13][N:12]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:10]=2)=[CH:4][CH:5]=1
Reactant: c1ccc(-c2nc(N3CCNCC3)no2)cc1
Reactant: O=C(O)c1ccncc1
Agent: Cl
Product: c1cc(-c2nc(N3CCNCC3)no2)ccn1

Procedure:
The title product was prepared following the procedure of Intermediate 11 (step a to d) but using isonicotinic acid in step c). The title compound was obtained as a solid. TLC—Chloroform/methanol (8/2): Rf=0.2. HPLC purity: 97%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C[C:16]([N:18]([CH3:20])[CH3:19])=O.O>CN(C=O)C>[Cl:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6](/[CH:8]=[CH:16]/[N:18]([CH3:20])[CH3:19])[CH:7]=1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)/C=C/c1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 72.4 %

Procedure:
A mixture of 1-chloro-5-methyl-2,4-dinitro-benzene (11.6 g, 50.0 mmol), DMA (11.9 g, 100 mmol) in DMF (50 mL) was heated at 100° C. for 4 h. The solution was cooled and poured into water. The precipitated red solid was collected by filtration, washed with water, and dried to give (E)-2-(5-chloro-2,4-dinitrophenyl)-N,N-dimethylethenamine (9.84 g, 72%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.C(N(CC)CC)C.[C:22](Cl)(=[O:31])[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[C:10]([O:9][C:8]([NH:7][C@@H:3]1[CH2:4][CH2:5][CH2:6][N:1]([C:22]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:31])[CH2:2]1)=[O:14])([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of (R)-tert-butyl piperidin-3-ylcarbamate (10.00 g, 49.93 mmol) and triethylamine (20.88 mL, 149.8 mmol) in CH2Cl2 (100 mL) at 0° C. (ice bath) was treated dropwise with benzyl carbonochloridate (10.54 mL, 74.90 mmol) and stirred at 0° C. After 2 hours, the mixture was diluted with CH2Cl2 (50 mL) and successively washed with ice cold 10% HCl (2×30 mL), water (1×30 mL), saturated NaHCO3 (1×30 mL), and brine (1×30 mL) The organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The residue obtained was purified by flash chromatography on silica gel (Biotage Flash 60) eluting with 20% EtOAc/hexane (3 L). The fractions containing the product were pooled, concentrated in vacuo and dried under high vacuum for 18 hours to provide (R)-benzyl 3-(tert-butoxycarbonylamino)piperidine-1-carboxylate as a solid. LCMS (APCI+) m/z 335 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([OH:19])=[O:18].[C:20](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:1][C:2]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:20])[CH:11]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([OH:19])=[O:18]
Reactant: Cc1c(CC(=O)O)ccc2c1Cc1cc(O)ccc1-2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc2c(c1)Cc1c-2ccc(CC(=O)O)c1C

Procedure:
A mixture of 59mg. of methyl 7-hydroxyfluorene-2-acetic acid, 1.3g. of potassium carbonate, and 0.5ml. methyl iodide in 11ml. of acetone is refluxed for 22 hr., filtered and the solid washed with additional acetone. The filtrate is evaporated and the residue plate chromatographed on silica gel employing chloroform-hexane (2:1) as the developing solvent. Elution of the least polar band with ethyl acetate, evaporation and crystallization of the residue from ethyl acetate-isopropyl ether gives 17mg. of the title compound, mp 114-115°. Recrystallization from ethyl acetate-isopropyl ether gives the analytical sample, mp 114.5°-115.5°; λKBr 5.80μ.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH3:14][C:15]1[C:20]([CH2:21][OH:22])=[CH:19][CH:18]=[C:17]([C:23]([F:26])([F:25])[F:24])[N:16]=1.[CH3:27][O:28][C:29](=[O:42])[CH2:30][C:31]1[C:35]2[C:36]([F:41])=[CH:37][C:38](O)=[CH:39][C:34]=2[S:33][CH:32]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH3:27][O:28][C:29](=[O:42])[CH2:30][C:31]1[C:35]2[C:36]([F:41])=[CH:37][C:38]([O:22][CH2:21][C:20]3[C:15]([CH3:14])=[N:16][C:17]([C:23]([F:24])([F:26])[F:25])=[CH:18][CH:19]=3)=[CH:39][C:34]=2[S:33][CH:32]=1
Reactant: Cc1nc(C(F)(F)F)ccc1CO
Reactant: COC(=O)Cc1csc2cc(O)cc(F)c12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)Cc1csc2cc(OCc3ccc(C(F)(F)F)nc3C)cc(F)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
To a mixture of tri-n-butylphosphine (0.655 mL), (2-methyl-6-(trifluoromethyl)pyridin-3-yl)methanol (167 mg), methyl(4-fluoro-6-hydroxy-1-benzothiophen-3-yl)acetate (210 mg) and THF (dry) (15 mL) was added ADDP (662 mg, 2.62 mmol) at room temperature. The mixture was stirred at room temperature for 2 h and then concentrated in vacuo. To the residue was added IPE and the insoluble materials were removed by filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, EtOAc/hexane) and silica gel column chromatography (EtOAc/hexane) to give the title compound (310 mg). The crystals were recrystallized from acetone-hexane.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)=[N:9][C:10]3[N:11]([N:13]=[CH:14][CH:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([N:30]2[C:34]3=[N:35][CH:36]=[N:37][C:38]([NH2:39])=[C:33]3[CH:32]=[N:31]2)[CH2:26][CH2:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]1([C:7]2[C:8]([C:16]3[CH:23]=[CH:22][C:19]([CH2:20][N:24]4[CH2:29][CH2:28][CH:27]([N:30]5[C:34]6=[N:35][CH:36]=[N:37][C:38]([NH2:39])=[C:33]6[CH:32]=[N:31]5)[CH2:26][CH2:25]4)=[CH:18][CH:17]=3)=[N:9][C:10]3[N:11]([N:13]=[CH:14][CH:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-c2nc3ccnn3cc2-c2ccccc2)cc1
Reactant: Nc1ncnc2c1cnn2C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Nc1ncnc2c1cnn2C1CCN(Cc2ccc(-c3nc4ccnn4cc3-c3ccccc3)cc2)CC1
Reaction time: 8 h
Yield: 25.6 %

Procedure:
250 mg (0.84 mmol) 4-(6-phenylpyrazolo[1,5-a]pyrimidin-5-yl)benzaldehyde and 257 mg (1 mmol) 1-piperidine-4-yl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine were treated as previously described. Additional NaBH(OAc)3 has been added after one, two and three hours (two equivalents each). After a further stirring at room temperature additional 26 mg 1-piperidine-4-yl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine and two equivalents NaBH(OAc)3 were added. After stirring overnight and two further additions of NaBH(OAc)3 the solvents were evaporated. Workup und purification yields 108 mg of the desired compound.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:36](Cl)(=[O:40])[CH:37]([CH3:39])[CH3:38]>>[CH3:38][CH:37]([CH3:39])[C:36]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]3)=[O:15])=[CH:11][CH:12]=2)[CH2:2][CH2:3]1)=[O:40]
Reactant: CC(C)C(=O)Cl
Reactant: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCNCC4)cc3)cc(=O)c2c1
Product: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCN(C(=O)C(C)C)CC4)cc3)cc(=O)c2c1

Procedure:
This compound was prepared from 6-methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (Example 43) and commercially available isobutyryl chloride (Aldrich) via the parallel synthesis described above. MS−base peak at m/z=548 by positive ion CI.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]([NH2:9])[C:6](=[NH:8])[NH2:7])[CH3:2].[F:11][C:12]([F:22])([F:21])[C:13](=O)[C:14](=O)[C:15]([F:18])([F:17])[F:16]>>[NH2:8][C:6]1[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:10])=[N:9][C:14]([C:15]([F:18])([F:17])[F:16])=[C:13]([C:12]([F:22])([F:21])[F:11])[N:7]=1
Reactant: O=C(C(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)C(N)C(=N)N
Product: CCOC(=O)c1nc(C(F)(F)F)c(C(F)(F)F)nc1N

Procedure:
The title compound was prepared from amino-carbamimidoyl-acetic acid ethyl ester (Intermediate B2) and 1,1,1,4,4,4-hexafluorobutane-2,3-dione analogously to Intermediate B; 10 LCMS Rt=4.72 minutes, [M+H]+ 304.2/326.1 Method 10 minLC_v002.
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12](=[O:37])[CH:13](OS(C3C=CC(C)=CC=3)(=O)=O)[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:8]=2)[O:3]1.[F-:39].[K+]>C(#N)C.O>[CH3:1][C:2]1([CH3:38])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12](=[O:37])[CH:13]([F:39])[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:8]=2)[O:3]1
Reactant: COc1cc(C(OS(=O)(=O)c2ccc(C)cc2)C(=O)c2ccc3c(c2)CCC(C)(C)O3)cc(OC)c1OC
Reactant: [F-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc(C(F)C(=O)c2ccc3c(c2)CCC(C)(C)O3)cc(OC)c1OC
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
To a solution of toluene-4-sulfonic acid 2-(2,2-dimethyl-chroman-6-yl)-2-oxo-1-(3,4,5-trimethoxy-phenyl)-ethyl ester (21.6 mg, 0.04 mmol) in anhydrous ACN (0.5 mL) is added KF (4.72 mg, 0.08 mmol) and Kryptofix (30.6 mg, 0.08 mmol). After completion of addition the reaction mixture is heated to 90° C. After 15 minutes, the reaction mixture is cooled down to room temperature and diluted with water. The aqueous layer is separated and extracted with ethyl acetate (3×). All combined organic layers are dried over Na2SO4, filtered, and concentrated to yield an oil. The crude material is purified using reverse phase to yield the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].CCN(C(C)C)C(C)C>N1C=CC=CC=1>[CH3:21][S:22]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)(=[O:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2N)CC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2NS(C)(=O)=O)CC1
Yield: 72.1 %

Procedure:
tert-Butyl 4-{2-[(methylsulfonyl)amino]phenyl}-piperazinecarboxylate was prepared following the procedure for Preparation III using, tert-butyl 4-(2-aminophenyl)piperazinecarboxylate (4.4 g, 16 mmol), methanesulfonyl chloride (1.4 mL, 18 mmol) and DIEA (instead of pyridine) (3.1 mL, 18 mmol). The crude material was purified by flash chromatography (SiO2, 4:1 hexane:EtOAc) and concentrated in vacuo to afford the desired compound (4.1 g). MS (ESI, pos. ion) m/z: 356 (M+H), (ESI, neg. ion) m/z: 354 (M−H). Calc'd for C16H25N3O4S: 355.16.