Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]([CH3:12])[CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[N:19]=[CH:18][N:17]=[C:16]2[N:20]([CH:32]3[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]3)[N:21]=[C:22]([C:23]3[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([O:30][CH3:31])[CH:24]=3)[C:15]=12>ClCCl.N1C=CC=CC=1>[NH2:13][C:14]1[N:19]=[CH:18][N:17]=[C:16]2[N:20]([CH:32]3[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]3)[N:21]=[C:22]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:9](=[O:10])[CH2:8][C@H:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH3:12])=[C:25]([O:30][CH3:31])[CH:24]=3)[C:15]=12
Reactant: C[C@H](CC(=O)Cl)c1ccccc1
Reactant: COc1cc(-c2nn(C3CCC(=O)CC3)c3ncnc(N)c23)ccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-c2nn(C3CCC(=O)CC3)c3ncnc(N)c23)ccc1NC(=O)C[C@@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.8 %

Procedure:
(3R)-3-phenylbutanoyl chloride (2.22 g, 12.18 mmol) in dichloromethane (10 mL) was added to a solution of 4-[4-amino-3-(4-amino-3-methoxyphenyl)-1H -pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclohexanone (2.86 g, 8.12 mmol) in pyridine (50 mL) at −10° C. After 15 minutes, the ice-water bath was removed and the reaction mixture was stirred at room temperature overnight. Sodium hydroxide (1.0N, 15 mL) was added and the organic solvent was evaporated. The aqueous residue was extracted with dichloromethane. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichlromethane/methanol (95:5) as mobile phase to give N1-{4-[4-amino-1-(4-oxocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-(3R)-3-phenylbutanamide (3.11 g, 77%). 1H NMR (CDCl3) δ 1.40 (d, J=6.97 Hz, 3H), 2.04 (m, 1H), 2.59-2.78 (m, 9H), 3.40 (m, 1H), 3.98 (s, 3H), 5.28 (m, 1H), 5.70 (bs, 2H), 7.15-7.35(m, 7H), 7.66 (s, 1H), 8.38 (s, 1H), 8.51 (d, J=8.18, 1H). HPLC (Waters Alliance-Column: Waters SymmetryShield, RP18, 3.5 um, 2.1×50 mm. Eluents: 5% B/A to 95% B/A in 9.0 min.(B: acetonitrile, A: 100 mM ammonia acetate buffer, pH 4.5), 0.5 mL/min.): Rt=6.273 min.
Reaction SMILES: C([N:5]1[CH2:10][CH2:9][C:8](=[O:11])[C:7](C(OC)=O)([CH3:12])[CH2:6]1)(OC)=O.[BrH:17]>CO>[BrH:17].[CH3:12][CH:7]1[C:8](=[O:11])[CH2:9][CH2:10][NH:5][CH2:6]1
Reactant: COC(=O)N1CCC(=O)C(C)(C(=O)OC)C1
Agent: Br
Solvent: CO
Product: CC1CNCCC1=O
Temperature: 25 °C

Procedure:
A solution of 1,3-dicarbomethoxy-3-methyl-4-piperidone (51.45 g, 225 mmol) in hydrobromic acid (48%, 250 mL) is heated under reflux for 4 h and then cooled to room temperature. The resultant solution is concentrated in vacuo to give an orange colored solid. The solid is suspended in methanol (50 mL) and concentrated in vacuo again to give 3-methyl-4-piperidone hydrobromide salt: 42.9 g; 98%; mp 203°-205° C.
Reaction SMILES: [CH3:1][N:2]([CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[CH2:3][CH2:4][C:5]#[C:6][C:7]([CH2:11][CH3:12])(O)[CH2:8][CH3:9].C(N(CC)CC)C.S(Cl)(C)(=O)=O>C(Cl)Cl>[CH3:1][N:2]([CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[CH2:3][CH2:4][C:5]#[C:6][C:7]([CH2:11][CH3:12])=[CH:8][CH3:9]
Reactant: CCC(O)(C#CCCN(C)Cc1cccc2ccccc12)CC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC=C(C#CCCN(C)Cc1cccc2ccccc12)CC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 630 mg N-methyl-N-(1-naphthylmethyl)-5-ethyl-5-hydroxy-3-heptyn-amine in CH2Cl2 are added, dropwise, at -20° 0.5 ml triethylamine and thereafter 0.21 ml mesylchloride, dissolved in CH2Cl2. The mixture is stirred for 3 hours at room temperature, washed several times with water, the organic phase is dried and evaporated. The residue is chromatographed over silica gel (with toluene/ethylacetate 4/1) to give the title compound (Compound 29) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH:19]12[CH2:25][CH:22]([CH2:23][CH2:24]1)[CH2:21][CH:20]2[NH2:26]>>[CH:19]12[CH2:25][CH:22]([CH2:23][CH2:24]1)[CH2:21][CH:20]2[NH:26][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][N:17]=[CH:18][C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: NC1CC2CCC1C2
Product: O=C(NC1CC2CCC1C2)c1ccncc1Nc1ccc(I)cc1F

Procedure:
N-bicyclo[2.2.1]hept-2-yl-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.31 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.45 mmol of bicyclo[2.2.1]hept-2-ylamine. LC/MS [10.01 min; 452 (M+1)]
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.N1C=CN=C1.Cl[Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20].CCOC(C)=O>CN(C=O)C.O>[CH:19]([Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[O:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1)([CH3:21])[CH3:20]
Reactant: O=C1COc2cc(O)ccc21
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)[Si](Oc1ccc2c(c1)OCC2=O)(C(C)C)C(C)C
Reaction time: 1 h

Procedure:
To a solution of 9.8 g (65.3 mMol) 6-hydroxy-2H-benzofuran-3-one in 80 ml DMF, 10.6 g (157 mMol) imidazole and 16.6 ml (78.3 mMol) chloro-triisopropylsilane are added dropwise. After 1 h, the mixture is poured into 300 ml EtOAc and 300 ml water, the aq. phase is separated off and extracted with 3×100 ml EtOAc. The organic layers are washed 4 times with 10% citric acid solution, brine and dried (Na2SO4). Then char coal is added. Filtration, concentration and drying (10 mbar, 65-85° C.) give the oily title compound: MS: [M+1]+=307; TLC(hexane/EtOAc 2:1): Rf=0.61.
Reaction SMILES: C([O:4][C@H:5]1[CH:22]=[CH:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[OH:4][C@H:5]1[CH:22]=[CH:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1
Reactant: CC(=O)O[C@H]1C=C[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C[C@]12C=C[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of compound 6 (0.25 g) and potassium carbonate (0.3 g) in methanol-water (15 ml, 9:1) was stirred at room temperature for 8 hr. Solution was concentrated diluted with cold water, cooled and the precipitated solid was filtered, and crystallized from methanol. White solid, mp. 138-40° C.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.C[O:16][B:17](OC)[O:18]C.[OH-].[Na+]>O1CCCC1>[CH3:14][S:13][C:10]1[CH:11]=[CH:12][C:7]([B:17]([OH:18])[OH:16])=[CH:8][CH:9]=1
Reactant: CSc1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CSc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
Under nitrogen, 113 mL (181 mmol) of n-BuLi (1.6M in hexanes) was added to a stirred solution of 30 g (150 mmol) of 4-bromothioanisole (Lancaster) in 1,500 mL of anhydrous tetrahydrofuran (THF) at --78° C. After 30 minutes, 51 mL (450 mol) of trimethylborate was added. The reaction was warmed to ambient temperature and stirred overnight. The resulting solution was treated with 300 mL of 10% NaOH and stirred vigorously for 1 hour. The THF was removed in vacuo, the pH adjusted to 4-5 and the solid collected by filtration. The solid was washed repeatedly with water and hexane. Drying in vacuo gave 21 g (83%) of 4-methylthiophenylboronic acid as a colorless solid: NMR (DMSO-d6) δ 2.47 (s, 3H), 7.20 (d, J=8 Hz, 2H), 7.71 (d, J=8 Hz, 2H), 7.96 s,
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH2:27][CH3:28])=[N:7][N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14](/[CH:18]=[CH:19]/[C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH:13]=2)[C:9]=1[CH2:10][CH3:11])=[O:4].[OH-].[Li+]>C1COCC1.CO>[Cl:26][C:23]1[CH:24]=[CH:25][C:20](/[CH:19]=[CH:18]/[C:14]2[CH:13]=[C:12]([N:8]3[C:9]([CH2:10][CH3:11])=[C:5]([C:3]([OH:4])=[O:2])[C:6]([CH2:27][CH3:28])=[N:7]3)[CH:17]=[CH:16][CH:15]=2)=[CH:21][CH:22]=1
Reactant: CCc1nn(-c2cccc(/C=C/c3ccc(Cl)cc3)c2)c(CC)c1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1nn(-c2cccc(/C=C/c3ccc(Cl)cc3)c2)c(CC)c1C(=O)O
Temperature: 25 °C
Yield: 98.6 %

Procedure:
A solution of 1.78 g (4.5 mmol) of 1-{3-[(E)-2-(4-chloro-phenyl)-vinyl]-phenyl}-3,5-diethyl-1H-pyrazole-4-carboxylic acid methyl ester in 100 ml of THF/MeOH (1:1) was treated with 11.3 ml of lithium hydroxide solution (1 M in water) at RT and then stirred at reflux (boiling temperature=80° C.) for 60 hours. The reaction mixture was then cooled to RT and evaporated. The residue was partitioned between water and CH2Cl2, acidified with HCl (2N) to pH 1-2 and extracted twice with CH2Cl2. The organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated to give 1.69 g of crude title compound as light yellow solid. MS: 379.2 ([M−H]−, 1 Cl).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([OH:13])=O)=[CH:4][C:3]=2[O:2]1.NCC1CCN(CC2C=CC(Cl)=C(Cl)C=2)C1.[NH2:30][CH2:31][CH:32]1[CH2:36][CH2:35][N:34]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]3[O:44][CH2:45][O:46][C:40]=3[CH:39]=2)[CH2:33]1>>[CH2:45]1[O:44][C:41]2[CH:42]=[CH:43][C:38]([CH2:37][N:34]3[CH2:35][CH2:36][CH:32]([CH2:31][NH:30][C:11](=[O:13])[CH2:10][C:5]4[CH:6]=[CH:7][C:8]5[O:9][CH2:1][O:2][C:3]=5[CH:4]=4)[CH2:33]3)=[CH:39][C:40]=2[O:46]1
Reactant: NCC1CCN(Cc2ccc3c(c2)OCO3)C1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Agent: NCC1CCN(Cc2ccc(Cl)c(Cl)c2)C1
Product: O=C(Cc1ccc2c(c1)OCO2)NCC1CCN(Cc2ccc3c(c2)OCO3)C1

Procedure:
Proceeding as described above but substituting 4-(2,5-dimethylphenyl)-4-oxobutyric acid with 2-(3,4-methylenedioxyphenyl)acetic acid and 3-aminomethyl-1-(3,4-dichlorobenzyl)pyrrolidine with 3-aminomethyl-1-(3,4-methylenedioxybenzyl)pyrrolidine gave N-[1-(3,4-methylenedioxybenzyl)pyrrolidin-3-(RS)-ylmethyl]-2-(3,4-methylenedioxyphenyl)acetamide.
Reaction SMILES: C1C2C(COC([NH:18][C@@H:19]([CH2:34][C:35]3[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[NH:37][CH:36]=3)[C:20]([NH:22][C@@H:23]([CH2:27][S:28][S:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([OH:26])=[O:25])=[O:21])=O)C3C(=CC=CC=3)C=2C=CC=1.C1CCN2C(=NCCC2)CC1>CN(C)C=O>[NH2:18][C@@H:19]([CH2:34][C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[NH:37][CH:36]=1)[C:20]([NH:22][C@@H:23]([CH2:27][S:28][S:29][C:30]([CH3:32])([CH3:31])[CH3:33])[C:24]([OH:26])=[O:25])=[O:21]
Reactant: CC(C)(C)SSC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)SSC[C@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)O
Temperature: 25 °C
Yield: 90.6 %

Procedure:
A solution of the prepared (R)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1H-indol-3-yl)propanamido)-3-(tert-butyldisulfanyl)propanoic acid (Fmoc-Trp-Cys(StBu)-OH) (Compound SP602) (500 mg, 0.809 mmol) in N,N-dimethylformamide (1.6 mL) was mixed with 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) (134 μL, 0.890 mmol) with stirring at room temperature, and the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (R)-2-((S)-2-amino-3-(1H-indol-3-yl)propanamido)-3-(tert-butyldisulfanyl)propanoic acid (H-Trp-Cys(StBu)-OH) (Compound SP639) (290 mg, 0.733 mmol, 91%).
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH2:7][NH:8][C:9]([C:11]2[C:12]3[CH:19]=[N:18][N:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[C:13]=3[CH:14]=[N:15][CH:16]=2)=[O:10])=[CH:5][N:6]=1.[CH3:27][O-:28].[Na+].CO>CS(C)=O>[CH3:27][O:28][C:2]1[S:3][C:4]([CH2:7][NH:8][C:9]([C:11]2[C:12]3[CH:19]=[N:18][N:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[C:13]=3[CH:14]=[N:15][CH:16]=2)=[O:10])=[CH:5][N:6]=1
Reactant: C[O-]
Reactant: O=C(NCc1cnc(Br)s1)c1cncc2c1cnn2-c1ccc(F)cc1
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: COc1ncc(CNC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)s1
Temperature: 50 °C

Procedure:
To a solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid (2-bromo-thiazol-5-ylmethyl)-amide (30 mg, 0.07 mmol) in DMSO (5 mL) was added a 0.5 M solution of NaOMe in MeOH (2.0 mL, 1.0 mmol). The solution was warmed at 50° C. and after 48 hours, was partitioned between saturated aqueous sodium bicarbonate (50 mL) and EtOAc (50 mL). The organic phase was separated and washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography eluting with a gradient of 0-10% methanol in dichloromethane. The material was further purified by preparative thin layer silica gel chromatography eluting with methanol-dichloromethane (2:98) to afford the title compound.
Reaction SMILES: Br[C:2]1[C:3]([CH3:11])=[N:4][N:5]([CH3:10])[C:6]=1[C:7]([OH:9])=O.C1COCC1.B.C1COCC1.[Cl:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[C:26]([O:31][CH3:32])[C:25]=1[C@H:33]([C:35]1[C:43]2[C:38](=[N:39][CH:40]=[C:41](B3OC(C)(C)C(C)(C)O3)[CH:42]=2)[NH:37][CH:36]=1)[CH3:34].C([O-])([O-])=O.[K+].[K+].O>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCOCC1>[Cl:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[C:26]([O:31][CH3:32])[C:25]=1[C@H:33]([C:35]1[C:43]2[C:38](=[N:39][CH:40]=[C:41]([C:2]3[C:3]([CH3:11])=[N:4][N:5]([CH3:10])[C:6]=3[CH2:7][OH:9])[CH:42]=2)[NH:37][CH:36]=1)[CH3:34]
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Cc1nn(C)c(C(=O)O)c1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: B
Solvent: O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3c(C)nn(C)c3CO)cc12
Temperature: 60 °C

Procedure:
To a solution of 4-bromo-1,3-dimethyl-1H-pyrazole-5-carboxylic acid (20.0 mg, 0.0913 mmol) in THF (3 mL, 30 mmol) was added 1.0 M of BH3.THF in THF (0.456 mL, 0.456 mmol), and the mixture was heated to 60° C. overnight. The material was extracted with EtOAc, and washed with sat. NaHCO3 (3×). The organic layer was concentrated in vacuo. 3-[(S)-1-(2-Chloro-3-fluoro-6-methoxyphenyl)-ethyl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (15.0 mg, 0.0348 mmol), (1,1′bis-(diphenylphosphino)-ferrocene) palladium dichloride (3.34 mg, 0.00456 mmol), K2CO3 (18.9 mg, 0.137 mmol) and 4:1 dioxane:H2O (1 mL, 10 mmol) were added, and the mixture was heated to 95° C. for 30 min. The solution was used directly for HPLC purification, and the fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.80 (d, J=7.1 Hz, 3H), 2.04 (s, 3H), 3.64 (br. s., 3H), 3.89 (s, 3H), 4.46 (s, 2H), 5.05-5.15 (m, 1H), 6.88 (dd, J=9.1, 4.3 Hz, 1H), 7.07 (t, J=8.8 Hz, 1H), 7.36 (s, 1H), 7.38 (br. s., 1H), 8.07 (d, J=2.0 Hz, 1H). MS (ES+): m/z=429.14/431.15 (100/50) [MH+]. HPLC: tR=1.38 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[C:8]([NH:10][CH:11]2[CH2:13][CH2:12]2)[N:7]2[N:14]=[CH:15][C:16]([CH:17]=[O:18])=[C:6]2[N:5]=1)=[N+]=[N-]>[Pd].C(O)C>[NH2:1][C:4]1[CH:9]=[C:8]([NH:10][CH:11]2[CH2:13][CH2:12]2)[N:7]2[N:14]=[CH:15][C:16]([CH:17]=[O:18])=[C:6]2[N:5]=1
Reactant: [N-]=[N+]=Nc1cc(NC2CC2)n2ncc(C=O)c2n1
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(NC2CC2)n2ncc(C=O)c2n1
Reaction time: 6 h
Yield: 85 %

Procedure:
The above product 5-azido-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (1.09 g, 4.46 mmol) was subjected to hydrogenation using 10% wt palladium on carbon in ethanol. The reaction was stirred under hydrogen for 6 hours. The mixture was filtered through celite and sonicated with 1:1 mixture of ethyl acetate and hexane. The light yellow solid was filtered and dried to yield 5-amino-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde as product 750 mg (85% yield). LCMS (M+1=218)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:18])[CH:10]=[CH:11]C1C=CC=CC=1.[Al+3].[Cl-].[Cl-].[Cl-]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[N:8]=[C:9]([OH:18])[CH:10]=[CH:11]2
Reactant: O=C(C=Cc1ccccc1)Nc1ccccc1F
Agent: [Al+3]
Agent: [Cl-]
Product: Oc1ccc2cccc(F)c2n1
Temperature: 160 °C
Reaction time: 8 h
Yield: 106.2 %

Procedure:
N-(2-Fluorophenyl)cinnamamide (97.2 g, 403 mmol) was combined with AlCl3 (161 g, 1209 mmol) and the solids were thoroughly mixed. The dry mixture was heated to 160° C. for 100 minutes. The reaction was cooled and quenched by addition of ice. A beige solid formed after complete dispersion of the dark solids and this was stirred overnight. The beige solid was filtered and air-dried overnight to provide the desired product as a free-flowing solid (69.8 g).
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]([C:10]#[N:11])[C:8]#[N:9])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:17][CH2:18][C:19]([F:22])([F:21])[F:20]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]([CH2:17][CH2:18][C:19]([F:22])([F:21])[F:20])([C:8]#[N:9])[C:10]#[N:11])=[CH:12][CH:13]=1
Reactant: N#CC(C#N)Cc1ccc(F)cc1
Reactant: FC(F)(F)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(F)cc1
Yield: 21.9 %

Procedure:
Using 1.00 g of (4-fluorobenzyl)malononitrile, 15 ml of N,N-di-methylformamide, 0.23 g of sodium hydride (60% in oil), and 1.02 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.34 g of 2-(4-fluorobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (16)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][Br:22])[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: BrCCCCCCBr
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(CCCCCCBr)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from compound 1 and 1,6-dibromohexane as described for compound 58. Purified by chromatography [ethyl acetate/petroleum ether (60-80° C.), 1:2]. Crystallized from petroleum ether (60-80° C.). M.p. 74-75° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]([CH3:18])([CH3:17])[C:13]([O:15]C)=O)[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][CH3:10].[F:19][C:20]([F:33])([F:32])[C:21]1[CH:28]=[C:27]([N:29]=[C:30]=[S:31])[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]>CS(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([N:11]2[C:12]([CH3:18])([CH3:17])[C:13](=[O:15])[N:29]([C:27]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:20]([F:33])([F:19])[F:32])[CH:28]=3)[C:30]2=[S:31])[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][CH3:10]
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Reactant: COCc1ccc(NC(C)(C)C(=O)OC)cc1F
Solvent: O
Solvent: CS(C)=O
Product: COCc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)cc1F
Yield: 4.6 %

Procedure:
The title compound was prepared according to General Method 1. A solution of methyl 2-(3-fluoro-4-(methoxymethyl)phenylamino)-2-methylpropanoate (60 mg, 0.24 mmol) and 2-(trifluoromethyl)-4-isothiocyanatobenzonitrile (120 mg, 0.52 mmol) in DMSO (1 mL) was heated at 82° C. for 12 h. The reaction mixture was poured in water (10 mL) and extracted with ethyl acetate. The organic layer was dried over Na2SO4, concentrated under reduced pressure and purified by silica gel chromatography (100-200 mesh) to obtain 5 mg of final product, HPLC, Column: YMC ODS AQ, 4.6×250 mm, 5 μm, Mobile Phase A: 0.05% TFA, Mobile Phase B: ACN, Gradient: 10% to 90% B in 10 min, hold for 10 min. 90% to 10% B in 1 min, Flow Rate: 1 mL/min, Retention time: 13.316 min, M+1, 452.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8](N2CCN(C3C(Cl)=CN=CC=3Cl)CC2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[Cl:25]C1C=NC=C(Cl)C=1N1CCNCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([Cl:25])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cncc(Cl)c1N1CCNCC1
Reactant: O=S(=O)(c1cccc(Cl)c1)N1CCN(c2c(Cl)cncc2Cl)CC1
Product: O=S(=O)(Cl)c1cccc(Cl)c1
Yield: 66 %

Procedure:
In an analogous manner to Example 1F, step 1Q 1-[(3-chlorophenyl)sulfonyl]-4-(3,5-dichloropyridin-4-yl)piperazine was prepared from 1-(3,5-dichloro-4-pyridyl)piperazine (0.1 g, 0.43 mmol) and 3-chlorobenzene sulfonyl chloride (66% yield).
Reaction SMILES: Cl[CH2:2][C:3](=[CH2:15])[CH2:4][C:5]#[C:6][C:7]([CH3:14])=[CH:8][CH2:9][CH2:10][C:11](=[O:13])[CH3:12].[CH3:16][C:17]([OH:21])([C:19]#[CH:20])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C>[OH:21][C:17]([CH3:18])([CH3:16])[C:19]#[C:20][CH2:2][C:3](=[CH2:15])[CH2:4][C:5]#[C:6][C:7]([CH3:14])=[CH:8][CH2:9][CH2:10][C:11](=[O:13])[CH3:12]
Reactant: C#CC(C)(C)O
Reactant: C=C(CCl)CC#CC(C)=CCCC(C)=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Product: C=C(CC#CC(C)=CCCC(C)=O)CC#CC(C)(C)O
Temperature: 25 °C
Reaction time: 25 h
Yield: 77 %

Procedure:
A mixture of 118 mg (0.52 mmole) of 10-chloromethyl-6-methyl-5,10-undecadien-7-yn-2-one (produced in accordance with Example III), 46 mg (0.55 mmole) of 2-methyl-3-butyn-2-ol (purchased from Aldrich Chemical Co., Milwaukee, Wis.), 125 mg (0.90 mmole) of anhydrous potassium carbonate, 12 mg (0.12 mmole) of cuprous chloride, and 13 mg (0.057 mmole) of benzyltriethylammonium chloride in 0.75 mL of acetonitrile (HPLC-grade, purchased from Aldrich Chemical Co., Milwaukee, Wis.) was stirred vigorously at room temperature for 25 hours, during which time the mixture was maintained under an atmosphere of nitrogen. Isolation of the product as described in the procedure of Example III afforded, after removal of the volatile organic solvents at reduced pressure, 109 mg (77% yield) of the named C-18 ketone. The proton NMR spectrum of this compound exhibited a singlet at δ1.50 [6H's, C(CH3)2 ], a singlet at δ1.77 (CH3 bonded to C-6), a singlet at δ2.12 (CH3C=O), and two singlets at δ2.97 and 3.04 (4H's, hydrogens bonded to C-11 and C-9).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:17][CH3:18])=[C:4]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.C[O:20][C:21](=O)[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([N:29]2[CH:33]=[C:32]([C:34]3[CH:35]=[N:36][N:37]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:38]=3[CH2:39][CH3:40])[N:31]=[CH:30]2)[CH:23]=1>>[C:8]([C:6]1[CH:5]=[C:4]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:3]([O:17][CH3:18])=[C:2]([NH:1][C:21](=[O:20])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([N:29]3[CH:33]=[C:32]([C:34]4[CH:35]=[N:36][N:37]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[C:38]=4[CH2:39][CH3:40])[N:31]=[CH:30]3)[CH:23]=2)[CH:7]=1)([CH3:10])([CH3:11])[CH3:9]
Reactant: CCc1c(-c2cn(-c3cc(C(=O)OC)ccc3C)cn2)cnn1-c1ccccc1
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Product: CCc1c(-c2cn(-c3cc(C(=O)Nc4cc(C(C)(C)C)cc(NS(C)(=O)=O)c4OC)ccc3C)cn2)cnn1-c1ccccc1

Procedure:
Example 158 was prepared from N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide and 3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzoic acid methyl ester (Example 151) in the same manner as Example 151. ESI MS m/z 627 [C34H38N6O4S+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][OH:19])=[CH:13][CH:12]=2)=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8].[C:20](Cl)(=[O:25])[CH2:21][CH:22]([CH3:24])[CH3:23]>>[CH3:23][CH:22]([CH3:24])[CH2:21][C:20]([O:19][CH2:18][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([N:10]2[C:3]3=[N:4][C:5]([CH3:9])=[CH:6][C:7]([CH3:8])=[C:2]3[N:1]=[C:3]2[CH2:2][CH:7]([CH3:8])[CH3:6])=[CH:12][CH:13]=1)=[O:25]
Reactant: Cc1cc(C)c(N)c(Nc2ccc(CCO)cc2)n1
Reactant: CC(C)CC(=O)Cl
Product: Cc1cc(C)c2nc(CC(C)C)n(-c3ccc(CCOC(=O)CC(C)C)cc3)c2n1

Procedure:
The title compound was prepared according to the procedure described in step 5 of Example 1 from 2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol (step 4 of Example 1) and isovaleryl chloride.