Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[N:21][OH:22])[NH2:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.[C:38](C1NC=CN=1)(C1NC=CN=1)=[O:39].N12CCCN=C1CCCCC2>O1CCOCC1>[CH:1]1([C:4]2[C:5]([N:24]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)[S:25]([CH3:28])(=[O:26])=[O:27])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]4[NH:20][C:38](=[O:39])[O:22][N:21]=4)[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: COc1ccc(CN(c2cc3oc(-c4ccc(F)cc4)c(C(N)=NO)c3cc2C2CC2)S(C)(=O)=O)cc1
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(CN(c2cc3oc(-c4ccc(F)cc4)c(-c4noc(=O)[nH]4)c3cc2C2CC2)S(C)(=O)=O)cc1
Yield: 79.7 %

Procedure:
A mixture of Example 8C (2.62 g, 5.0 mmol), carbonyl diimidazole (0.973 g, 6.00 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.829 mL, 5.50 mmol) in dioxane (20 mL) was refluxed for one hour, cooled and partitioned between ethyl acetate and 1 M aqueous HCl. The organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated. The residue was triturated with ethyl acetate/hexane (1:3) to give the title compound as a solid (2.19 g, 80%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[N:18]#[C:19][NH2:20].FC(F)(F)S(O)(=O)=O>C1COCC1>[C:19](=[NH:18])([O:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:10][CH:11]=1)[NH2:20]
Reactant: OCCc1ccc(Oc2ccc(F)cc2)cc1
Reactant: N#CN
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCOC1
Product: N=C(N)OCCc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.7 %

Procedure:
To a solution of 2-{4-[(4-fluorophenyl)oxy]phenyl}ethanol (750 mg, 3.23 mmol) and cyanamide (149 mg, 3.55 mmol) in THF (15 mL) was added trifluoromethanesulfonic acid (0.344 mL, 3.88 mmol) at 0° C. The reaction mixture was stirred at room temperature overnight. After removing the solvent, the residue was diluted with water, extracted with DCM. The organic phase was dried over sodium sulfate, filtered, and concentrated. Purification via reverse phase flash chromatography then afforded the title compound (290 mg, 1.057 mmol, 32.7% yield).
Reaction SMILES: N[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:23][C@H:22]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]2[O:13][C:14](=[O:16])[CH3:15])=[C:4]([Cl:29])[N:3]=1.O.N(OC(C)(C)C)=[O:32]>C(O)(C)(C)C>[Cl:29][C:4]1[N:3]=[C:2]([OH:32])[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[C@@H:11]1[O:23][C@H:22]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)(C)ON=O
Solvent: CC(C)(C)O
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(O)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Amino-6-chloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine (42.7 g, 100 mmoles) is dissolved in 2 liters of a tert-butyl alcohol:water mixture (1:1, v/v) with heating. After cooling the solution with an ice bath, tert-butyl nitrite (50 mL, 422 mmoles) is added in one portion. The ice bath is removed and the mixture is stirred at room temperature until gas evolution ceases (approximately 3 hours). The mixture is then frozen (dry ice/2-propanol) and lyophilized to afford the desired intermediate as a yellow solid that is used immediately or stored frozen at −20° C. without purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[N:5][CH:4]=1.O.O.O.[C:18]([O-])(=[O:20])[CH3:19].[Na+].C(OC(=O)C)(=O)C>O>[Cl:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:10][CH2:11][N:12]([C:18](=[O:20])[CH3:19])[CH2:13][CH2:14]2)[CH:6]=[N:5][CH:4]=1
Reactant: CC(=O)[O-]
Reactant: Clc1cncc(N2CCNCC2)n1
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)N1CCN(c2cncc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6-Chloro-2-(1-piperazinyl)-pyrazine hydrochloride (15 g, 0.064 mole) is added to a solution of 20 g of sodium acetate trihydrate (0.147 mole) in 250 ml ice water. The vigorously stirred mixture is treated with 15 ml acetic anhydride followed by 100 ml water. The mixture is stirred 3 hours while warming to room temperature and the product, which separates as an oil, is extracted with toluene. The toluene extract is washed with water and concentrated in vacuo to give a crude product which is recrystallized twice from n-butylchloride to give the title compound, mp 106°-107.5° C.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH:28]([C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](O)=[O:39])=[CH:33][CH:32]=1)([CH3:30])[CH3:29].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C([O-])(O)=O.[Na+]>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]([C:38](=[O:39])[CH2:37][C:34]2[CH:35]=[CH:36][C:31]([CH:28]([CH3:29])[CH3:30])=[CH:32][CH:33]=2)[CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(CC(=O)O)cc1
Reactant: CCCCOC(=O)c1ccc2c(c1)CCC2N[C@H]1CC[C@H](C(C)(C)C)CC1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOC(=O)c1ccc2c(c1)CCC2N(C(=O)Cc1ccc(C(C)C)cc1)[C@H]1CC[C@H](C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of enantiomer A of butyl 1-[(trans-4-tert-butylcyclohexyl)amino]indane-5-carboxylate, (41 mg, 0.11 mmol) in CH2CL2 (3 mL) was added (4-isopropylphenyl)acetic acid (98 mg, 0.55 mmol), EDC (105 mg, 0.55 mmol), HOBt (74 mg, 0.55 mmol) and DIEA (200 μL, 1.10 mmol). After stirring at room temperature for 18 h, the reaction mixture was poured into saturated aqueous NaHCO3 (10 mL) and extracted with EtOAc (20 mL). The organic layer was washed with brine (2×10 mL), dried over Na2SO4, filtered and concentrated. Chromatography (10% EtOAc in Hexane) gave butyl 1-{(trans-4-tert-butylcyclohexyl)[(4-isopropylphenyl)acetyl]amino}indane-5-carboxylate. HPLC/MS: m/z=532.3 (M+1), Rt=3.15 min.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C=O.[C:18](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:18][N:6]1[CH2:7][C@@H:2]([CH3:1])[N:3]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][C@H:5]1[CH3:8]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@H](C)CN1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccccc2)[C@H](C)CN1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
To a solution of (2R,5R)-2,5-dimethyl-1-(phenylmethyl)piperazine (prepared according to J. Med. Chem. 2006, 49, 716-726, utilizing N-Boc-D-alanine in place of N-Boc-L-alanine) (667 mg, 3.26 mmol) in dichloromethane (25 mL) at 0° C. was added formaldehyde (0.367 mL, 37% water solution, 4.89 mmol) followed by sodium triacetoxyborohydride (900 mg, 4.24 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2 h before being diluted with dichloromethane and washed with 1N NaOH solution. The organics were washed with brine, dried (MgSO4) and evaporated to yield (2R,5R)-1,2,5-trimethyl-4-(phenylmethyl)piperazine (680 mg, 96%). LCMS: (M+H)+: 219.1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.CO[CH:11]=[C:12]1[C:17](=[O:18])[O:16][C:15]([CH3:20])([CH3:19])[O:14][C:13]1=[O:21]>C(O)(C)C>[Cl:8][C:3]1[C:2]([NH:1][CH:11]=[C:12]2[C:13](=[O:21])[O:14][C:15]([CH3:19])([CH3:20])[O:16][C:17]2=[O:18])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Nc1cccnc1Cl
Reactant: COC=C1C(=O)OC(C)(C)OC1=O
Solvent: CC(C)O
Product: CC1(C)OC(=O)C(=CNc2cccnc2Cl)C(=O)O1
Yield: 89.9 %

Procedure:
A suspension of 3-amino-2-chloropyridine (17.6 g) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (25.5 g) in isopropanol (274 ml) was heated to reflux for 5 minutes. After cooling, the deposit was filtrated to obtain 5-((2-chloropyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (34.8 g). The obtained 5-((2-chloropyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-di one (8.2 g) was gradually added to Dowtherm heated to 220° C., and the mixture was heated at 220° C. for 30 minutes. After cooling, hexane (300 ml) was added to the reaction solution, and the deposit was filtrated to obtain 8-chloro-1,7-naphthyridin-4(1H)-one (2.02 g). 4-(4-Chloro-1,7-naphthyridin-8-yl)-2-(ethylamino)benzonitrile (0.107 g) was obtained according to Example 5(1) using the obtained 8-chloro-1,7-naphthyridin-4(1H)-one (0.295 g) instead of compound (3a) and 4-cyano-3-(ethylamino)phenylboronic acid pinacol ester instead of 3-quinolineboronic acid. A suspension of the obtained 4-(4-chloro-1,7-naphthyridin-8-yl)-2-(ethylamino)benzonitrile (0.0491 g), 4-(1H-imidazol-4-yl)-1-methyl-1H-pyrazole hydrochloride (0.035 g), copper(II) oxide nanoparticles (0.06 g), and potassium carbonate (0.0883 g) in DMF (1.5 ml) was stirred overnight at 125° C. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with brine. The organic layer thus washed was dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain 2-(ethylamino)-4-(4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1,7-naphthyridin-8yl)benzonitrile. An aqueous sodium hydroxide solution (4 M, 0.093 mL) and a 30% aqueous hydrogen peroxide solution (0.045 mL) were added to a solution of the obtained 2-(ethylamino)-4-(4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1,7-naphthyridin-8yl)benzonitrile in DMSO (3 mL) at room temperature, and the mixture was stirred for 30 minutes. Water was added to the reaction solution, and the deposit was collected by filtration, then washed with water and ether by sprinkling, and then dried under reduced pressure to obtain compound (72) (0.040 g, yield based on 6 steps: 4%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([C:15]([CH2:26][CH3:27])([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:25])[CH:19]=3)[CH2:16][CH3:17])=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2].Br[CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].C([O-])([O-])=O.[K+].[K+]>>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:20]([CH3:25])[CH:19]=3)([CH2:26][CH3:27])[CH2:16][CH3:17])=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(C(CC)(CC)c3ccc(O)c(C)c3)ccc2o1
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1cc2cc(C(CC)(CC)c3ccc(OCC(=O)C(C)(C)C)c(C)c3)ccc2o1
Yield: 84.3 %

Procedure:
5-[1-Ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-benzofuran-2-carboxylic acid ethyl ester (7.10 g, 19.4 mmol) and 1-bromopinacolone (4.17 g, 23.3 mmol) and K2CO3 (5.35 g, 38.8 mmol) are reacted analogous to Example 1E to give the title compound as a pale yellow oil (7.60 g, 84%).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10])([CH3:5])[CH:3]=[O:4].[C:15](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:5][C:2]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([O:11][CH3:15])=[O:10])([CH3:1])[CH:3]=[O:4]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C=O)c1cccc(C(=O)O)c1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1cccc(C(C)(C)C=O)c1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a solution of 3-(l,l-dimethyl-2-oxoethyl)benzoic acid in acetone (60 mL) were added potassium carbonate (3.78 g, 27.3 mmol) and methyl iodide (3.40 mL, 54.6 mmol), and the mixture was stirred at 60° C. for 5 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. To the obtained residue was added saturated aqueous sodium hydrogen carbonate solution (50 mL), and the mixture was extracted with ethyl acetate (100 mL, 30 mL). The combined organic layer was washed with saturated brine (20 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give methyl 3-(1,1-dimethyl-2-oxoethyl)benzoate as a yellow oil.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][CH2:27][NH2:28])[CH:22]=[CH:23][C:24]=1[Cl:25]>>[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][CH2:27][NH:28][CH2:14][C:13]2[CH:16]=[CH:17][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:11][CH:12]=2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: NCCc1ccc(Cl)c(Cl)c1
Reactant: CCCCCCCCOc1ccc(C=O)cc1
Product: CCCCCCCCOc1ccc(CNCCc2ccc(Cl)c(Cl)c2)cc1

Procedure:
The same procedure as employed in the preparation of Example 394 (step b) but using 4-(octyloxy)benzaldehyde and 2-(3,4-dichlorophenyl)ethylamine gave the title compound as an oil. HPLC (Condition A), Rt: 4.69 min (HPLC purity: 71.8%).
Reaction SMILES: C1C=CC2N=C[NH:9][C:7](=[O:8])C=2C=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([CH3:22])=O)=[C:15]([CH3:23])[CH:14]=1>>[CH3:22][C:20]1[NH:9][C:7](=[O:8])[C:17]2[C:16](=[C:15]([CH3:23])[CH:14]=[C:13]([CH3:12])[CH:18]=2)[N:19]=1
Reactant: CC(=O)Nc1ccc(C)cc1C
Reactant: O=c1[nH]cnc2ccccc12
Product: Cc1cc(C)c2nc(C)[nH]c(=O)c2c1

Procedure:
The quinazolinone used as starting material was obtained using the first part of the process described in Example 1 concerning the preparation of starting materials except that 2,4-dimethylacetanilide was used in place of 3,4-dimethylacetanilide. Only one isomer, 3,4-dihydro-2,6,8-trimethylquinazolin-4-one, was obtained. Sodium hydride (2.39 g) was added to a stirred suspension of the product thus obtained (9.3 g) in dimethylformamide (100 ml) and the mixture was stirred at laboratory temperature for 1 hour. A solution of chloromethyl pivalate (8.23 ml) in dimethylformamide (20 ml) was added and the mixture was stirred at laboratory temperature for 18 hours, then poured onto a mixture of ice water (350 ml). The precipitate was filtered off, dried and purified by chromatography on a silica gel column using methylene chloride as eluent. There was thus obtained 3,4-dihydro-2,6,8-trimethyl-3-pivaloyloxymethylquinazolin-4-one (8.7 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:2][CH2:3][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[C:6](=[O:23])[N:7]([CH:15]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]2=[O:22])[C:8]([CH3:14])=[N:9]3)=[O:30])=[CH:27][CH:26]=1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(CNC(=O)c3ccc(Cl)cc3)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.48 g, 1.4 mmol) in acetonitrile (10 mL), was added 4-chloro-benzoyl chloride (0.27 mL, 2.2 mmol) and N,N-diisopropyl ethylamine (0.62 mL, 3.6 mmol). The mixture was stirred at room temp overnight. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 4-chloro-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-benzamide as a white solid (390 mg, 62% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 6.18 min (98.0%); mp, 276-278° C.; 1HNMR (DMSO-d6)2.18-2.23 (m, 1H, CHH), 2.58-2.93 (m, 6H, CHCH2, CH3), 4.97-5.08 (m, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.33-7.96 (m, 7H, Ar), 9.01 (t, 1H, J=6 Hz, CH2NH), 11.05 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.82, 23.29, 30.60, 42.21, 56.54, 117.66, 124.16, 125.52, 128.45, 129.17, 132.95, 133.95, 136.13, 140.69, 148.52, 154.84, 161.10, 165.23, 169.54, 172.63. LCMS MH=439, 441; Anal Calcd For C22H19N4O4Cl+0.1H2O: C, 59.96; H, 4.39; N, 12.71; Cl, 8.05. Found: C, 59.80; H, 4.13; N, 12.61; Cl, 8.30.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH2:20])=[O:19])=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C([BH3-])#N.[Na+]>C(O)(=O)C>[F:21][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH2:20])=[O:19])=[C:13]3[NH:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: NC(=O)c1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: NC(=O)c1cnn2c1NCC=C2c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A 10.0 g amount of 7-(3-(trifluoromethyl) phenyl)pyrazolo(1,5-a)pyrimidine-3-carboxamide (prepared in the manner described in Example 1) is stirred under nitrogen as a suspension in 120 ml of glacial acetic acid (cooled in an ice bath) and then 5.5 g of sodium cyanoborohydride is added to the reaction mixture in portions with an additional 80 ml of glacial acetic acid. After one hour of stirring in the ice bath the mixture is stirred at room temperature for 19 hours. The solution is evaporated to dryness, then water is added and the white precipitate which forms is collected by filtration and washed with an aqueous saturated solution of sodium bicarbonate, then with water. The solid is treated with 100 ml of acetonitrile, isolated and dried to give 5.25 g of the desired product, which is recrystallized from acetonitrile, mp 157-160° C.
Reaction SMILES: [NH2:1][C@H:2]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:3]([NH:5][CH:6]1[CH2:15][C:14]2[C:9](=[C:10]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])[CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:22][C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[C:7]1=[O:28])=[O:4].[C:33]([O:37][C:38]([NH:40][C@:41]([CH3:47])([CH2:45][CH3:46])[C:42](O)=[O:43])=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[CH3:47][C@@:41]([NH:40][C:38](=[O:39])[O:37][C:33]([CH3:36])([CH3:35])[CH3:34])([CH2:45][CH3:46])[C:42]([NH:1][C@H:2]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:3](=[O:4])[NH:5][CH:6]1[CH2:15][C:14]2[C:9](=[C:10]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])[CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:22][C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[C:7]1=[O:28])=[O:43]
Reactant: CC(C)C[C@@H](N)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Reactant: CC[C@@](C)(NC(=O)OC(C)(C)C)C(=O)O
Product: CC[C@@](C)(NC(=O)OC(C)(C)C)C(=O)N[C@H](CC(C)C)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Yield: 97.8 %

Procedure:
The procedure of Example 14(a) was repeated, except that (2R)-2-amino-4-methyl-N-[2-oxo-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-yl]pentanamide (600 mg) and (R)-2-(tert-butoxycarbonylamino)-2-methylbutanoic acid (320 mg) were used, whereby tert-butyl (2R)-2-methyl-1-[(2R)-4-methyl-1-oxo-1-[2-oxo-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-ylamino]pentan-2-ylamino]-1-oxobutan-2-ylcarbamate (844 mg) was yielded. Subsequently, the procedure of Example 25(a) was repeated, except that the compound prepared as described above was used, whereby the title compound (528 mg) was yielded.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([OH:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[OH:4].[CH:11]([C:13]1(O)[CH2:16][CH2:15][CH2:14]1)=[CH2:12]>O1CCOCC1.C(OCC)(=O)C>[CH3:10][C:5]1[C:3]([OH:4])=[C:2]([CH3:1])[CH:8]=[C:7]2[C:6]=1[CH2:12][CH2:11][C:13]1([O:9]2)[CH2:16][CH2:15][CH2:14]1
Reactant: Cc1cc(O)cc(C)c1O
Reactant: C=CC1(O)CCC1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc2c(c(C)c1O)CCC1(CCC1)O2
Yield: 38.7 %

Procedure:
To a solution of 2,6-dimethylhydroquinone (2.36 g) and BF3-ether (4.47 mL) in dioxane (10 mL) was added 1-vinyl-cyclobutanol (1.58 g) in dioxane (5 mL) over 50 min at 110° C. under nitrogen. The reaction was refluxed for one additional hour. The solution was diluted with ethyl acetate and washed with water and brine, dried and evaporated. The residue was chromatographed (silica gel, hexane-ethyl acetate 1% to 5%) gave 1.36 g of 5,7-dimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-ol.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH:14][CH2:15][C:16]([OH:18])=[O:17])[CH:5]=[CH:4][C:3]1=2.S(Cl)(Cl)=O.[CH3:24]O>>[CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([NH:14][CH2:15][C:16]([O:18][CH3:24])=[O:17])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(NCC(=O)O)ccc21
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CNc1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
8 g (22 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylglycine and 100 ml of methanol were introduced into a round-bottomed flask and 9 ml (0.12 mol) of thionyl chloride were added dropwise. The mixture was stirred at room temperature for 12 hours, the reaction medium evaporated, and the residue taken up in sodium bicarbonate solution and ethyl ether. The organic phase was decanted off, dried over magnesium sulfate and evaporated. 6 g (100%) of the expected ester were recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[CH:20]=[CH:19][NH:18][C:17](=[O:21])[CH:16]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:23](I)[CH3:24]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[CH:20]=[CH:19][N:18]([CH2:23][CH3:24])[C:17](=[O:21])[CH:16]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cc[nH]c(=O)c1
Reactant: CCI
Solvent: CC(C)=O
Product: CCn1ccc(-n2cc(C#Cc3cccc(Cl)c3)nc2C)cc1=O

Procedure:
The title compound, orange gum, MS: m/e=338.3, 340.2 (M+H+), was prepared in accordance with the general method of example 2 from 4-[4-(3-chloro-phenylethynyl)-2-methyl-imidazol-1-yl]-1H-pyridin-2-one and ethyl iodide in acetone instead of DME.