Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC=C(OC)[C:27]=1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C(B2OC(C)(C)C(C)(C)O2)=CCC1>CN(C=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[C:29]1[C:28]([CH3:27])([CH3:33])[CH2:32][CH2:31][CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: COC(=O)c1ccc(OCc2ccccc2)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)CCC=C1B1OC(C)(C)C(C)(C)O1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OCc2ccccc2)c(C2=CCCC2(C)C)c1
Temperature: 75 °C
Reaction time: 21 h
Yield: 386.5 %

Procedure:
A stirred mixture of T7.3 (3.75 g, 11.66 mmol), ground S-Phos (0.96 g, 2.33 mmol), palladium acetate (0.26 g, 1.17 mmol), and potassium phosphate, tribasic (6.19 g, 29.17 mmol) in DMF (28.0 mL) and water (1.50 mL) was purged three times with argon and placed under vacuum three times. Before heating, 2-(5,5-dimethylcyclopent-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (T6.3) (3.11 g, 13.99 mmol) was added via syringe, then the mixture was heated to 75° C. After 21 hours (black solution), the reaction was cooled to room temperature, diluted with water, and extracted three times with EtOAc. The combined organic layers were washed twice with brine. After drying over anhydrous sodium sulfate and filtration, the organic solvent was removed under reduced pressure. The residue was purified on silica gel (0-10% EtOAc in hexanes) to yield T7.4 as a colorless oil (3.03 g, 77%). MS ESI (pos.) m/e: 337.0 (M+H)+.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Cl[CH2:7][CH:8]1[CH2:12][S:11][C:10]2([CH2:16][CH2:15][CH:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13]2)[S:9]1>CN(C=O)C.O>[C:1]([S:3][CH2:7][CH:8]1[CH2:12][S:11][C:10]2([CH2:16][CH2:15][CH:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13]2)[S:9]1)(=[O:4])[CH3:2]
Reactant: CC([O-])=S
Reactant: CCOC(=O)CC1CCC2(C1)SCC(CCl)S2
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCC2(C1)SCC(CSC(C)=O)S2
Yield: 103.5 %

Procedure:
A mixture of potassium thioacetate (5.4 g, 0.047 mole) and a solution of the product of Example E (4.0 g, 0.013 mole) in DMF (40 ml) was stirred under nitrogen for 2 days at room temperature. The reaction mixture was diluted with water (200 ml) and extracted twice with ethyl acetate. The organic phase was washed with brine and dried (Na2SO4). The drying agent was filtered and the filtrate stripped on the rotary evaporator to give 4.5 g of the titled compound. This material was a single spot on TLC.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][CH2:8][C:9]2=[N:14]O)=[NH:4].N[N:17]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N:19]=[C:18]1[NH2:29]>Cl>[ClH:28].[ClH:28].[OH:1][NH:2][C:3]([C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][CH2:8][C:9]2=[N:14][N:17]1[CH:21]=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[N:19]=[C:18]1[NH2:29])=[NH:4]
Reactant: N=C(NO)c1cccc2c1CCC2=NO
Reactant: Nc1nc(-c2ccc(Cl)cc2)cn1N
Agent: Cl
Product: N=C(NO)c1cccc2c1CCC2=Nn1cc(-c2ccc(Cl)cc2)nc1N
Temperature: 120 °C

Procedure:
A mixture of 1.026 g (5 mmol) of 4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 1.043 g (5 mmol) of 1,2-diamino-4-(4-chlorophenyl)-imidazole (see Beyer H. et al., Chem. Ber. 101, 3151 (1968)) and 20 ml of 4N hydrochloric acid is heated at 120° C. for 18 hours, with stirring, and is then concentrated by evaporation in vacuo. 25 ml of ethanol are added to the crystalline residue, the mixture is cooled to 5° C., with stirring, and is filtered, and the crystallizate is washed with a small amount of ethanol and diethyl ether. The crude title compound, dried under a high vacuum, contains 8.17% water and melts at 226°-228° C. (decomp.), 1H-NMR (D2O): δ=8.06 (d, 1H); 7.75 (d, 1H); 7.55 (t, 1H); 7.40 (s, 1H); 7.38 (d, 2H); 7.28 (d, 2H); 3.21-3.27 (m, 2H), 3.03-3.09 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>>[Si:14]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: Oc1cccc(-c2ccccn2)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Product: CC(C)(C)[Si](C)(C)Oc1cccc(-c2ccccn2)c1

Procedure:
Then, 2-(3-hydroxyphenyl)pyridine is treated with tert-butyldimethylsilyl chloride (TBDMSCl) to protect the OH group with a tert-butyldimethylsilyl group and give 2-(3-tert-butyldimethylsilyloxyphenyl)pyridine according to scheme (3).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[C:7]([NH:13]C(=O)C)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(=[O:4])[CH3:3]>C(O)C>[NH2:13][C:7]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([C:2](=[O:4])[CH3:3])[CH:6]=1
Reactant: COc1ccc(NC(C)=O)cc1C(C)=O
Agent: Cl
Solvent: CCO
Product: COc1ccc(N)cc1C(C)=O
Yield: 98.8 %

Procedure:
Hydrochloric acid (6M, 50 ml) was added to a mixture of N-(3-acetyl-4-methoxyphenyl)acetamide (10.34 g, 50 mmol) and ethanol (150 ml) and the mixture was stirred under reflux for 8 hours. The mixture was cooled and the solvent was evaporated under reduced pressure. Water (100 ml) was added and the pH was adjusted to 10.0 with saturated aqueous potassium carbonate. The mixture was extracted with dichloromethane (3×100 ml) and the combined organic fractions were dried (MgSO4) and evaporated under reduced pressure to give 1-(5-amino-2-methoxyphenyl)ethanone as a dark oil (8.16 g, 99%), 1H NMR (CDCl3) δ 7.09 (1H, d, J=2.8 Hz), 6.82 (2H, m), 3.84 (3H, s), and 3.34 (2H, br. s), 2.59 (3H, s). m/e (CI+) 166 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Cl.O.[C:12]([O:15]CC)(=[O:14])C>[I-].[Zn+2].[I-]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]([OH:6])[C:12]([OH:15])=[O:14]
Reactant: O=Cc1cccc(Cl)c1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [I-]
Agent: [Zn+2]
Solvent: O
Product: O=C(O)C(O)c1cccc(Cl)c1

Procedure:
A mixture of 158 g of 3-chlorobenzaldehyde, 111.6 g of trimethylsilylnitrile and a catalytic amount of zinc iodide was heated at 90° C. for 2 hours, with stirring. The reaction mixture was ice-cooled, and 350 ml of concentrated aqueous hydrochloric acid were added to it. The resulting mixture was then heated under reflux for 1 hour, after which it was mixed with water and with ethyl acetate. The ethyl acetate layer was separated and mixed with a 30% w/v aqueous solution of sodium hydroxide. The aqueous layer was separated, washed three times with ethyl acetate and then acidified with concentrated aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, to give the title compound as crystals, melting at 110°-114° C.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.[C:22]([C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1)#[N:23]>CC(N(C)C)=O.C(Cl)Cl>[C:22]([C:24]1[CH:25]=[C:26]([NH:30][C:31](=[O:32])[NH:1][C:2]2[CH:21]=[CH:20][C:5]([C:6]([NH:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:12][CH:11]=3)=[O:7])=[CH:4][CH:3]=2)[CH:27]=[CH:28][CH:29]=1)#[N:23]
Reactant: Nc1ccc(C(=O)NCc2ccc(S(N)(=O)=O)cc2)cc1
Reactant: N#Cc1cccc(N=C=O)c1
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: N#Cc1cccc(NC(=O)Nc2ccc(C(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Temperature: 0 °C
Yield: 75.9 %

Procedure:
4-Amino-N-(4-sulfamoylbenzyl)-benzamide (2.13 g, 1 eq.) was dissolved anhydrous in DMA (10 ml) under inert atmosphere, anhydrous DCM (30 ml) was added and the solution was cooled to 0° C. A solution of 3-cyanophenylisocyanate (1.9 g, 1.9 eq.) in anhydrous DCM (10 ml) was added and the mixture stirred over night. The resulting precipitate was filtered off, washed with methanol and dried in vacuo to yield 2.38 g (76%) 4-[3-(3-cyanophenyl)-ureido]-N-(4-sulfamoylbenzyl)-benzamide.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][N:10]=2)[CH:5]=[CH:6][N:7]=1.[H][H]>CCO.[Pd]>[C:11]1([C:8]2[N:4]3[CH2:5][CH2:6][NH:7][CH2:2][C:3]3=[N:10][N:9]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: [H][H]
Reactant: Clc1nccn2c(-c3ccccc3)nnc12
Agent: [Pd]
Solvent: CCO
Product: c1ccc(-c2nnc3n2CCNC3)cc1
Yield: 100.3 %

Procedure:
Title compound 472 (310 mg, 1.34 mmol) was dissolved in EtOH (25 mL) and 10% Pd/C (75 mg, 25% w/w) was added. The reaction mixture was stirred under 1 atmosphere of hydrogen over night. The catalyst was filtered and the filtrate was evaporated to afford title compound 473 (269 mg, 100%). MS (m/z): 201.1 (M+H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:30]2[CH2:42][CH2:41][N:33]3[C:34]4[CH2:35][CH2:36][CH2:37][CH2:38][C:39]=4[CH:40]=[C:32]3[C:31]2=[O:43])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:27]=[C:22]3[CH2:23][O:24][CH2:25][CH2:26][N:21]3[N:20]=2)[C:15](=[O:28])[N:14]([CH3:29])[CH:13]=1)(=O)C.[OH-].[Li+]>>[N:20]1[N:21]2[C:22]([CH2:23][O:24][CH2:25][CH2:26]2)=[CH:27][C:19]=1[NH:18][C:16]1[C:15](=[O:28])[N:14]([CH3:29])[CH:13]=[C:12]([C:11]2[CH:10]=[CH:9][N:8]=[C:7]([N:30]3[CH2:42][CH2:41][N:33]4[C:34]5[CH2:35][CH2:36][CH2:37][CH2:38][C:39]=5[CH:40]=[C:32]4[C:31]3=[O:43])[C:6]=2[CH2:5][OH:4])[CH:17]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCOC4)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2cc3n(n2)CCOC3)c1=O
Yield: 59.6 %

Procedure:
Following the procedures as described in Example 113, 129d (180 mg 0.31 mmol) was hydrolyzed with lithium hydroxide to give 129 as a white solid (100 mg, 62%). LCMS: [M+H]+ 542. 1H NMR (500 MHz, CDCl3) δ 8.48 (d, J=5.0, 1H), 7.98 (d, J=2.0, 1H), 7.71 (d, J=2.0, 1H), 7.46 (s, 1H), 7.35 (d, J=5.0, 1H), 6.89 (s, 1H), 5.72 (s, 1H), 5.03 (d, J=6.5, 1H), 4.79 (s, 2H), 4.61-4.64 (m, 1H), 4.50 (s, 1H), 4.31-4.35 (m, 1H), 4.06-4.16 (m, 6H), 3.86 (s, 1H), 3.71 (s, 3H), 2.56-2.62 (m, 4H), 1.88-1.92 (m, 2H), 1.80 (m, 2H)
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:28]#[N:29])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:27])=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>COCCO>[C:28]([C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:19][C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:27])=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:7])[N:9]=1)#[N:29]
Reactant: NCCC(=O)O
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3c(C)cccc3C)cc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: Cc1cccc(C)c1Oc1ccc2c(C#N)nc(C(=O)NCCC(=O)O)c(O)c2c1
Temperature: 25 °C
Yield: 58 %

Procedure:
A mixture of 1-cyano-6-(2,6-dimethyl-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (80 mg, 0.20 mmol), β-alanine (365 mg, 4.10 mmol) and NaOMe (166 mg, 3.07 mmol) in 2-methoxyethanol (10 mL) was refluxed for 2 h. After the mixture was cooled to r.t., solvent was evaporated. The residue was partitioned between EtOAc (50 mL) and water (50 mL). 1 M HCl was added with vigorous stirring until pH was ˜2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-60% EtOAc/hexanes+2% AcOH) to give 47 mg of the title compound. MS: (+) m/z 406.21 (M+1).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[CH2:22][CH2:21][CH2:20]2.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[CH:26]=[CH:25][C:24]2[C:23](=[O:27])[CH2:22][CH2:21][CH2:20][C:19]=2[CH:18]=1)(=[O:5])=[O:4]
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reaction time: 0.33 h

Procedure:
Trifluoromethanesulfonic anhydride (2.51 mL) was added to a solution of 6-hydroxy-3,4-dihydro-2H-naphthalen-1-one (2.00 g) and triethylamine (4.11 mL) in dichloromethane (20 mL) at −20° C., and the reaction solution was stirred at that temperature for 20 minutes. After confirming that the raw materials disappeared, the reaction solution was concentrated under reduced pressure, and water and chloroform were added to the residue and the organic layer was partitioned. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (elution solvent: heptane-ethyl acetate system) to obtain 3.30 g of the title compound. Properties data of the compound are as follows.
Reaction SMILES: [Br:1]Br.[C:3]1([C:9](=[C:12]([C:15]#[N:16])[C:13]#[N:14])[CH2:10][CH3:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(C1C=CC=CC=1)(=O)C>C1C=CC=CC=1>[Br:1][CH:10]([CH3:11])[C:9](=[C:12]([C:13]#[N:14])[C:15]#[N:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrBr
Reactant: CCC(=C(C#N)C#N)c1ccccc1
Solvent: c1ccccc1
Solvent: CC(=O)c1ccccc1
Product: CC(Br)C(=C(C#N)C#N)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2.7 ml of bromine are added to 9.1 g of 1-phenylpropylidene-propanedinitrile and 0.2 g of acetophenone in 100 ml of benzene and the mixture is stirred at room temperature for 1.5 hours. The residue obtained after evaporation under vacuum is recrystallised from 25 ml of ethanol. 11,7 g of 2-bromo-1-phenyl-propylidene-propanedinitrile melting at 103° to 104° C. are obtained.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[C:8]3[NH:16][N:15]=[N:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)=[CH:4][CH:3]=1.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][CH2:27][CH2:28][O:29][CH:30]([CH3:32])[CH3:31])[N:20]=1>>[CH:30]([O:29][CH2:28][CH2:27][O:26][CH2:25][C:21]1[N:20]=[C:19]([CH2:18][N:14]2[C:9]3[N:10]=[C:11]([NH2:13])[N:12]=[C:7]([C:5]4[O:6][C:2]([CH3:1])=[CH:3][CH:4]=4)[C:8]=3[N:16]=[N:15]2)[CH:24]=[CH:23][CH:22]=1)([CH3:32])[CH3:31]
Reactant: CC(C)OCCOCc1cccc(CBr)n1
Reactant: Cc1ccc(-c2nc(N)nc3nn[nH]c23)o1
Product: Cc1ccc(-c2nc(N)nc3c2nnn3Cc2cccc(COCCOC(C)C)n2)o1

Procedure:
Prepared from 7-(5-methyl-2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine and 2-bromomethyl-6-(isopropyloxyethoxymethyl)pyridine by the alkylation method described in Example 36.
Reaction SMILES: O[CH:2]([CH3:30])[C:3]#[C:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:19][N:18]=1)[CH2:9][CH2:8]2.[O:31]([C:38]([NH:40][O:41][C:42]([O:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:43])=[O:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[O:31]([C:38]([N:40]([O:41][C:42]([O:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:43])[CH:2]([CH3:30])[C:3]#[C:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)=[CH:19][N:18]=1)[CH2:9][CH2:8]2)=[O:39])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(O)C#Cc1ccc2c(c1)CCN(Cc1ccc(-c3ccc(F)cc3)cn1)C2=O
Reactant: O=C(NOC(=O)Oc1ccccc1)Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C#Cc1ccc2c(c1)CCN(Cc1ccc(-c3ccc(F)cc3)cn1)C2=O)N(OC(=O)Oc1ccccc1)C(=O)Oc1ccccc1
Reaction time: 16 h

Procedure:
To a chilled (0° C.) solution of 6-[3-hydroxy-1-butyn-1-yl]-2-{[5-(4-fluorophenyl)-2-pyridyl]-methyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline (510 mg, 1.3 mmol), N,O-bis(phenoxycarbonyl)hydroxylamine (390 mg, 1.4 mmol), and triphenylphosphine (0.42 g, 1.6 mmol) in THF (10 mL) is added a solution of diisopropyl azodicarboxylate (320 mg, 0.32 mL, 1.6 mmol) in THF (2 mL). After 16 hours, the reaction is concentrated in vacuo and the residue chromatographed (silica gel. 1:1 EtOAc/hexanes) to afford 6-{3-[N,O-bis(phenoxycarbonyl)hydroxylamino]-1-butyn-1-yl}-2-{[5-(4-fluorophenyl)-2-pyridyl]-methyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:27])[N:18]=[C:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:12]2[N:11]=1)[CH3:2].[S:28](Cl)([Cl:31])(=[O:30])=[O:29]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:28]([Cl:31])(=[O:30])=[O:29])=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:27])[N:18]=[C:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:12]2[N:11]=1)[CH3:2]
Reactant: CCCCCCCc1nc(C)c2c(=O)[nH]c(-c3ccccc3OCC)nn12
Reactant: O=S(=O)(Cl)Cl
Product: CCCCCCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nn12

Procedure:
The preparation is carried out analogously to the procedure of Example 27A using 0.3 g (0.81 mmol) of 2-(2-ethoxyphenyl)-5-methyl-7-heptyl-3H-imidazo-[5,1-f][1,2,4]triazin-4-one (Example 22A). This gives 0.3 g (78.9%) of sulphonyl chloride as a white foam which is directly reacted further.
Reaction SMILES: Cl.Cl.[C:3]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([O:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]([CH3:39])[C:22](=[O:38])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]2[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=2)[CH2:15][CH2:14]1)=[O:11].[N:46]1([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:52][CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>>[C:3]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([O:12][CH:13]1[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][N:21]([CH3:39])[C:22](=[O:38])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]2[CH:37]=[CH:36][C:32]([C:33]([N:49]3[CH2:50][CH2:51][CH2:52][N:46]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:47][CH2:48]3)=[O:34])=[CH:31][CH:30]=2)[CH2:17][CH2:18]1)=[O:11]
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: Cl
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1ccc(C(=O)N2CCCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 20 %

Procedure:
25 mL of 4 N hydrochloric acid-dioxane was added to the compound (1.01 g, 1.56 mmol) obtained in Example 15c, and the mixture was stirred at room temperature for 16 hours. The solvent of the reaction mixture was evaporated under reduced pressure to give crude 4-({6-[(2-{4-[(biphenyl-2-ylcarbamoyl)oxy]piperidin-1-yl}ethyl)(methyl)amino]-6-oxohexyl}amino)benzoate dihydrochloride as a white solid. The resulting crude carboxylic acid compound and tert-butyl 1,4-diazepane-1-carboxylate (500 mg, 2.50 mmol) were used to give the title compound (240 mg; yield, 20%) as a white solid according to the method described in Example 41a.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[CH3:25][O:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[CH:29][C:28]=1[NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:31]3[CH:30]=[CH:29][C:28]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[C:27]([O:26][CH3:25])[CH:32]=3)[C:10]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)OC(C)(C)C

Procedure:
cis-3-Iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (10 g, 22.66 mmol), tert-butyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (9.49 g, 27.17 mmol), palladium tetrakistriphenyphosphine (1.57 g, 1.36 mmol) and sodium carbonate (5.76 g, 54.38 mmol) were mixed with ethylene glycol dimethyl ether (180 mL) and water (90 mL). The reaction mixture was heated at reflux overnight. Organic solvent was removed under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by preparative thin layer column chromatography using dichloromethane/methanol (80:20) as mobile phase to give cis-tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)carbamate (10.859 g, 89%). 1H NMR (DMSO-d6) δ 1.49 (s, 9H), 1.58 (m, 2H), 1.71 (m, 2H), 2.08 (m, 2H), 2.17 (s, 3H), 2.45 (m, 4H), 2.38 (m, 4H), 2.45 (m, 3H), 3.87 (s, 3H), 4.80 (m, 1H), 7.22 (m, 2H), 7.91 (d, J=8.14, 1H), 8.04 (s, 1H), 8.22 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[H-].[Na+].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:30]3[C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH:35]=O)=[N:28][CH:27]=[N:26][C:25]=3[O:24][C:23]=2[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:18][CH:17]=1>C1COCC1.ClCCl.O>[CH3:1][O:2][C:3](=[O:4])/[CH:5]=[CH:35]/[CH2:34][CH2:33][CH2:32][NH:31][C:29]1[C:30]2[C:22]([C:19]3[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)=[C:23]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[O:24][C:25]=2[N:26]=[CH:27][N:28]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCC=O)c23)cc1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)/C=C/CCCNc1ncnc2oc(-c3ccccc3)c(-c3ccc(OC)cc3)c12
Reaction time: 1 h

Procedure:
Add 0.095 ml (0.588 mmol) trimethyl phosphonoacetate dropwise at RT to a suspension of 21.6 mg sodium hydride (60% dispersion in oil, approx. 0.539 mmol) in 2 ml THF. Stir the mixture for a further 1 h and then add 190 mg (0.49 mmol) 4-{[5-(4-methoxyphenyl)-6-phenylfuro-[2,3-d]pyrimidin-4-yl]amino}butanal. Stir overnight at RT and then dilute the mixture with dichloromethane and water. Wash the organic phase with saturated sodium chloride solution, dry, and concentrate under vacuum. The target compound is isolated from the raw product by preparative RP-HPLC (twice) (gradient: water/acetonitrile). 23.4 mg (10.8% of theor.) of the desired product is obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O.Cl[CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32]>O>[C:12]([C:7]1[CH:8]=[C:9]([S:11][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: C[Si](C)(C)CCl
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)c1cc(SC[Si](C)(C)C)cc(C(C)(C)C)c1O
Temperature: 25 °C
Yield: 33.9 %

Procedure:
Mix 2,6-di-t-butyl-4-mercaptophenol (2.4 g, 10 mmol), potassium carbonate (1.4 g, 10 mmol), and dimethylacetamide (50 mL) and stir at room temperature under argon atmosphere. Add chloromethyltrimethylsilane (1.3 g, 10 mmol) and stir overnight. Warm on a steam bath for 2 hours, cool, and dilute with water. Extract with ethyl ether, dry, evaporate to a light yellow solid (2.8 g) and recrystallize (CH3CN) to give 1.1 g (34%) of the title compound; mp 100°-101° C.