Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([C:10]2[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:11]=2[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=2[F:25])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:26]1([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42]O)[CH:37]=2)[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:28][CH2:27]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[C:1]([C:5]1[O:9][C:8]([C:10]2[CH:15]=[C:14]([O:16][CH2:42][C:38]3[CH:37]=[C:36]([CH:29]([CH:26]4[CH2:27][CH2:28]4)[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:41]=[CH:40][CH:39]=3)[CH:13]=[CH:12][C:11]=2[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=2[F:25])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(c1cccc(CO)c1)C1CC1
Reactant: COc1ccc(F)c(-c2ccc(O)cc2-c2nnc(C(C)(C)C)o2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(-c3nnc(C(C)(C)C)o3)c2)c1)C1CC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 63.1 %

Procedure:
To a solution of 2-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)-2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-ol (109 mg), ethyl 3-cyclopropyl-3-(3-(hydroxymethyl)phenyl)propanoate (95 mg) and triphenylphosphine (167 mg) in THF (3.0 mL) was added a 40% solution of diethyl azodicarboxylate in toluene (250 μL) at 0° C., and the mixture was stirred at room temperature for 23 hr. The solvent was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (115 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].[N+:9]([C:12]1[CH:31]=[CH:30][C:15]([C:16]2[O:17][C:18]3[C:23]([C:24](=[O:26])[CH:25]=2)=[CH:22][CH:21]=[CH:20][C:19]=3[C:27](Cl)=[O:28])=[CH:14][CH:13]=1)([O-:11])=[O:10]>C1C=CC=CC=1>[CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH:6][C:27]([C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[O:17][C:16]([C:15]1[CH:30]=[CH:31][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=1)=[CH:25][C:24]2=[O:26])=[O:28])[CH3:2]
Reactant: O=C(Cl)c1cccc2c(=O)cc(-c3ccc([N+](=O)[O-])cc3)oc12
Reactant: CCN(CC)CCN
Solvent: c1ccccc1
Product: CCN(CC)CCNC(=O)c1cccc2c(=O)cc(-c3ccc([N+](=O)[O-])cc3)oc12
Yield: 65.1 %

Procedure:
The same procedure as in Example 31 was performed employing 0.34 g of N,N-diethylethylenediamine and 4'-nitroflavone-8-carboxylic acid chloride (prepared from 1.00 g of 4'-nitroflavone-8-carboxylic acid and 1.40 ml of thionyl chloride) in 30 ml of benzene to give 0.78 g of yellow crystals, which were recrystallized from methanol as yellowish brown crystals, m.p. 207°-209° C.
Reaction SMILES: C([O:8][C:9]1[C:17]([O:18][CH2:19]C)=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([CH3:21])[NH:13]2)C1C=CC=CC=1.C(OC1C(OC)=CC=C2C=1C=C(C)N2)C1C=CC=CC=1>>[OH:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([CH3:21])[NH:13]2
Reactant: CCOc1ccc2[nH]c(C)cc2c1OCc1ccccc1
Agent: COc1ccc2[nH]c(C)cc2c1OCc1ccccc1
Product: COc1ccc2[nH]c(C)cc2c1O
Yield: 89 %

Procedure:
This compound is obtained according to the operating method described in Example 2c, in which the 4-benzyloxy-5-ethoxy-2-methylindole is replaced by 4-benzyloxy-5-methoxy-2-methylindole. Following the operating method of Example 2 a pale yellow powder is obtained (yield=89%, m.p.=118°-119° C.).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:16])=[NH:15])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[C:17]1([CH:23]([CH3:30])[C:24](=O)[CH2:25][C:26](=O)[CH3:27])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[O-]CC.[Na+]>C(O)C>[CH3:27][C:26]1[CH:25]=[C:24]([CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:30])[N:16]=[C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([N:3]3[CH:4]=[CH:5][N:6]=[C:2]3[CH3:1])=[CH:12][CH:11]=2)[N:15]=1
Reactant: CC(=O)CC(=O)C(C)c1ccccc1
Reactant: Cc1nccn1-c1ccc(NC(=N)N)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C(C)c2ccccc2)nc(Nc2ccc(-n3ccnc3C)cc2)n1
Yield: 1.4 %

Procedure:
1-(4-(2-Methyl-1H-imidazol-1-yl)phenyl)guanidine (953 mg, 4.43 mmol, example 9e), 5-phenylhexane-2,4-dione (842 mg, 4.43 mmol) and sodium ethoxide (301 mg, 4.43 mmol) in ethanol (5 mL) were heated in a microwave reactor at 100° C. for 15 minutes. The mixture was allowed to reach room temperature and the crude was purified by HPLC yielding 4-methyl-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-6-(1-phenylethyl)pyrimidin-2-amine (23.00 mg, 1.313%). MS (ES+) m/z 370.2 (M+H)+
Reaction SMILES: [CH:1]1([NH:4][C:5](=O)[O:6]C2C=CC=CC=2)[CH2:3][CH2:2]1.CS(C)=O.[C:18]1([C:24]2[NH:40][C:27]3[N:28]=[CH:29][N:30]=[C:31]([O:32][C:33]4[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=4)[C:26]=3[CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[CH:1]1([NH:4][C:5]([NH:39][C:36]2[CH:37]=[CH:38][C:33]([O:32][C:31]3[C:26]4[CH:25]=[C:24]([C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=5)[NH:40][C:27]=4[N:28]=[CH:29][N:30]=3)=[CH:34][CH:35]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(NC1CC1)Oc1ccccc1
Reactant: Nc1ccc(Oc2ncnc3[nH]c(-c4ccccc4)cc23)cc1
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1ccc(Oc2ncnc3[nH]c(-c4ccccc4)cc23)cc1)NC1CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 11.8 %

Procedure:
After adding 30 mg of phenyl cyclopropylcarbamate and 0.5 ml of dimethylsulfoxide to 40 mg of 4-(6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenylamine, the mixture was stirred at 80° C. for 4 hours. The mixture was returned to room temperature, water was added, liquid separation and extraction were performed with ethyl acetate, and the solid obtained by concentration to dryness was washed with ether to obtain 6 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]1[C:9]2[C:10](OS(C(F)(F)F)(=O)=O)=[CH:11][C:12]([O:14][Si](C(C)C)(C(C)C)C(C)C)=[CH:13][C:8]=2[S:7][CH:6]=1.[CH3:34][CH2:35]O>[Cl-].[Na+].O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]1[C:9]2[C:10]([CH:34]=[CH2:35])=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[S:7][CH:6]=1
Reactant: COC(=O)Cc1csc2cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(OS(=O)(=O)C(F)(F)F)c12
Reactant: CCO
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: O
Product: C=Cc1cc(O)cc2scc(CC(=O)OC)c12
Temperature: 110 °C
Reaction time: 0.25 h

Procedure:
To a mixture of methyl(4-(((trifluoromethyl)sulfonyl)oxy)-6-((triisopropylsilyl)oxy)-1-benzothiophen-3-yl)acetate (900 mg) and EtOH (3 mL) were added potassium vinyl(trifluoro)borate (252 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (140 mg) and TEA (0.476 mL) at room temperature, and the mixture was stirred at 110° C. with microwave irradiation for 15 min. The mixture was poured into brine at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, and dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (379 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][CH2:16][C:3]21[C:7](=[O:8])[N:6]([C:9]1[CH2:10][O:11][C:12](=[O:15])[C:13]=1[CH3:14])[CH2:5][CH2:4]2.[CH3:27]I>C(#N)C.[Ag]=O>[CH3:27][O:1][CH:2]1[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][CH2:16][C:3]21[C:7](=[O:8])[N:6]([C:9]1[CH2:10][O:11][C:12](=[O:15])[C:13]=1[CH3:14])[CH2:5][CH2:4]2
Reactant: CC1=C(N2CCC3(CCN(C(=O)OC(C)(C)C)CC3O)C2=O)COC1=O
Reactant: CI
Agent: O=[Ag]
Solvent: CC#N
Product: COC1CN(C(=O)OC(C)(C)C)CCC12CCN(C1=C(C)C(=O)OC1)C2=O
Temperature: 60 °C

Procedure:
To the mixture of tert-butyl 6-hydroxy-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (CIS) (2 g, 5.46 mmol) and silver oxide (1.391 g, 6.00 mmol) in acetonitrile (50 mL) was added methyl iodide (3.41 ml, 54.6 mmol). The mixture was heated at 60° C. in a sealed tube overnight. After it cooled to rt, the mixture was filtered and the filtrate was concentrated and the residue was purified by silica gel chromatography using ethyl acetate/hexane to give tert-butyl 6-methoxy-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (CIS, racemate). LC/MS: (M+1)+: 380.99. The racetmate was further separated on an AD chiral column give tert-butyl 6-methoxy-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (faster eluting, CIS), LC/MS: (M+1)+: 381.05, and tert-butyl 6-methoxy-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (slower eluting, CIS). LC/MS: (M+1)+: 381.01.
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[CH:5][C:4]([C:8]([OH:10])=[O:9])=[CH:3]1.[C:11](Cl)(=O)[CH3:12]>C(O)C>[CH2:11]([O:9][C:8]([C:4]1[CH:5]=[N:6][NH:7][C:2](=[O:1])[CH:3]=1)=[O:10])[CH3:12]
Reactant: O=C(O)c1cn[nH]c(=O)c1
Reactant: CC(=O)Cl
Solvent: CCO
Product: CCOC(=O)c1cn[nH]c(=O)c1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
The title compound from Example 18.3 (1.0 g, 7.13 mmol) was added to a solution of ethanol (16 mL) and acetyl chloride (4 mL) and the resulting suspension was heated to 75° C. and stirred overnight. The reaction mixture was concentrated, diluted with water and extracted with dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([F:19])([F:18])[C:15]([OH:17])=[O:16])[CH:12]=2)[C:7]([CH3:20])=[N:6]1.[OH-].[K+:27]>C(O)C>[Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([F:19])([F:18])[C:15]([O-:17])=[O:16])[CH:12]=2)[C:7]([CH3:20])=[N:6]1.[K+:27]
Reactant: Cc1nn(Cc2c(Cl)cccc2Cl)c2cc(C(F)(F)C(=O)O)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(Cc2c(Cl)cccc2Cl)c2cc(C(F)(F)C(=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of the compound [183] (89 mg) in ethanol (2 mL) was added an aqueous solution of 1N-potassium hydroxide (233 μL) at room temperature, and then the reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure to give the titled compound (98 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([N:13]=[N:14][N:15]=2)[C:5]2[C:10]([N:11]=1)=[C:9]([CH3:12])[CH:8]=[CH:7][CH:6]=2.C>C(O)C>[CH3:1][CH:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:12])[N:4]2[N:13]=[N:14][N:15]=[C:3]12
Reactant: Cc1cccc2c1nc(C)c1nnnn12
Solvent: CCO
Product: Cc1cccc2c1NC(C)c1nnnn1-2
Yield: 81 %

Procedure:
A solution of 1.5 g. of 4,6-dimethyltetrazolo[1,5-a]quinoxaline in 200 ml. of ethanol was hydrogenated as above at about 3 atmospheres over 150 mg. of 5 percent palladized charcoal for 17 hours. The reaction mixture was then filtered, and the filtrate was evaporated to dryness. The residue was taken up in ethyl ether and chromatographed on a silica gel column with ethyl ether as the eluting solvent. The product-containing fractions were evaporated to dryness and the residue was recrystallized from ethanol to recover 4,5-dihydro-4,6-dimethyltetrazolo[1,5-a]quinoxaline, m.p. 159°-61°C., in 81 percent yield. The product was identified by NMR analysis and by elemental analysis with the following results.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][N:9]([C:14]2[S:18][C:17]([C:19]([O:21]C(C)(C)C)=[O:20])=[CH:16][CH:15]=2)[S:10]([CH3:13])(=[O:12])=[O:11])[CH2:3][CH2:2]1.[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]>C(Cl)Cl>[F:29][C:28]([F:31])([F:30])[C:26]([OH:32])=[O:27].[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][N:9]([C:14]2[S:18][C:17]([C:19]([OH:21])=[O:20])=[CH:16][CH:15]=2)[S:10]([CH3:13])(=[O:11])=[O:12])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)c1ccc(N(CCN2CCOCC2)S(C)(=O)=O)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)N(CCN1CCOCC1)c1ccc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
To a solution of tert-butyl 5-(N-(2-morpholinoethyl)-methylsulfonamido)-thiophene-2-carboxylate (Int. 58) (1.3 g, 3.33 mmol) in DCM (50 ml), TFA (2.56 ml, 33.3 mmol) was added drop-wise at 0° C. and then the brown solution was stirred at RT overnight. Additional TFA (7.69 ml, 99.9 mmol) was added in two portions over 4 hours, cooling to 0° C. and stirring at RT. The volatiles were removed under vacuum to afford 5-(N-(2-morpholinoethyl)methylsulfonamido)thiophene-2-carboxylic acid 2,2,2-trifluoroacetic acid salt (Int. 59) (1.436 g, 3.21 mmol, MS/ESI+335.0 [MH]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)C(C)C)(C)C.[CH3:28][O:29][CH2:30]Cl>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:9](/[N:12]=[C:13]2/[N:14]=[CH:15][N:16]([CH2:28][O:29][CH3:30])[CH:17]=[CH:18]/2)(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=S(=O)(Nc1ccncn1)c1ccc(F)c(Cl)c1
Reactant: COCCl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COCn1cc/c(=N\S(=O)(=O)c2ccc(F)c(Cl)c2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.6 %

Procedure:
To 3-chloro-4-fluoro-N-pyrimidin-4-ylbenzenesulfonamide (Preparation 426, 73 mg, 0.25 mmol) in methylene chloride (2 mL) cooled at 0° C. was added N,N-diisopropylethylamine (0.066 mL, 0.38 mmol) and chloromethyl methyl ether (0.025 mL, 0.28 mmol). After stirring at room temperature for 18 hours, the reaction mixture was diluted with ethyl acetate, washed successively with 1N aqueous sodium hydroxide, water, saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to give 76 mg (90%) of the title compound as an orange oil and a mixture of three regioisomers that were not separated.
Reaction SMILES: [C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[CH3:9][O:10][CH:11]([O:20][CH3:21])[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14](Br)[CH:13]=1>COCCOCCOC>[CH3:9][O:10][CH:11]([O:20][CH3:21])[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:13]=1
Reactant: [O-]c1ccccc1
Reactant: COC(OC)c1ccc(F)c(Br)c1
Agent: [Na+]
Solvent: COCCOCCOC
Product: COC(OC)c1ccc(F)c(Oc2ccccc2)c1
Temperature: 155 °C
Reaction time: 7 h
Yield: 75.4 %

Procedure:
0.4 g of copper-I bromide and 43.5 g (0.375 mole) of sodium phenolate were added to 95 ml of diethylene glycol dimethyl ether (diglyme). The temperature of the mixture rose to about 80° C. To effect dehydration, 15 ml of diglyme (boiling point 160° C.) were distilled off under normal pressure. 57.3 g (0.23 mole) of 3-bromo-4-fluoro-benzaldehyde dimethyl acetal were then added dropwise in the course of 10 minutes, at 150°-155° C., and the reaction mixture was stirred for a further 7 hours at 155° C. Gas chromatography indicated that all of the precursor had then been converted. Subsequently, the solvent was distilled off at 40° C./10 mm Hg, the residue was dissolved in 300 ml of toluene and, after adding 10 g of "Celite" (Trade Mark) 545 as a filter aid, the mixture was filtered to remove the inorganic material. The filtrate was washed with twice 100 ml of 50% strength sodium hydroxide solution, the solvent was then stripped off in vacuo and the residue was distilled in vacuo. 45.5 g (75. of theory) of 3-phenoxy-4-fluoro-benzaldehyde dimethyl acetal were thus obtained in the form of a colorless oil with a boiling point of 128°-130° C./0.1 mm Hg.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[N:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6]=1[C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2].Br[CH2:29][C:30]([O:32][CH3:33])=[O:31]>>[C:1]([N:4]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[N:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6]=1[C:20](=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:29][C:30]([O:32][CH3:33])=[O:31])(=[O:3])[CH3:2]
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(NC(C)=O)c2ccc(Cl)cc21
Reactant: COC(=O)CBr
Product: CCOC(=O)n1c(C(=O)c2ccccc2)c(N(CC(=O)OC)C(C)=O)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in Example 146 from 3-acetylamino-2-benzoyl-6-chloro-1-(ethoxycarbonyl)indole (Example 2, step 2) and methyl bromoacetate.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:3]=1[C:4]#[N:5].CO>C1COCC1>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[C:3]=1[CH2:4][NH2:5]
Reactant: N#Cc1c(F)cccc1C(F)(F)F
Solvent: CO
Solvent: C1CCOC1
Product: NCc1c(F)cccc1C(F)(F)F
Temperature: 25 °C
Yield: 100 %

Procedure:
To 2-fluoro-6-(trifluoromethyl)benzonitrile (45 g, 0.238 mmol) in 60 mL of THF was added 1 M BH3:THF slowly at 60° C. and the resulting solution was refluxed overnight. The reaction mixture was cooled to ambient temperature. Methanol (420 mL) was added slowly and stirred well. The solvents were then evaporated and the residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4. Evaporation gave 1a as a yellow oil (46 g, 0.238 mmol). MS (CI) m/z 194.0 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH:7]([CH2:17][N:18]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:8][C:9]1([C:14](O)=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.[CH2:64]([O:66][C:67]([C@H:69]1[CH2:74][CH2:73][C@@H:72]([NH2:75])[CH2:71][CH2:70]1)=[O:68])[CH3:65]>ClCCl>[C:1]([O:5][C:6](=[O:33])[CH:7]([CH2:17][N:18]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:8][C:9]1([C:14](=[O:15])[NH:75][C@H:72]2[CH2:71][CH2:70][C@@H:69]([C:67]([O:66][CH2:64][CH3:65])=[O:68])[CH2:74][CH2:73]2)[CH2:10][CH2:11][CH2:12][CH2:13]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)[C@H]1CC[C@@H](N)CC1
Reactant: CC(C)(C)OC(=O)C(CN(Cc1ccccc1)Cc1ccccc1)CC1(C(=O)O)CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(CN(Cc3ccccc3)Cc3ccccc3)C(=O)OC(C)(C)C)CCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The t-butyl ester from step (b) above (11.97 g, 26.54 mmole) in dry dichloromethane (200 ml), under nitrogen, was treated with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (10.19 g, 53 mmole), 1-hydroxybenztriazole (3.94 g, 29 mmole), triethylamine (16.08 g, 22.15 ml, 159 mmole) and cis-4-aminocyclohexane-carboxylic acid ethyl ester hydrochloride (6.04 g, 20 mmole). After stirring overnight at room temperature, the solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed with dilute hydrochloric acid (2×), dilute aqueous sodium bicarbonate, water, dried (Na2SO4) and evaporated to yield the crude product (15.5 g). This was chromatographed on silica (400 g) eluting with 1 to 10% diethyl ether in dichloromethane. Evaporation of the desired fractions gave 3-{1-[(cis-4-ethoxycarbonyl-cyclohexyl)-carbamoyl]cyclopentyl}-2-(dibenzylaminomethyl)propanoic acid t-butyl ester as an oil (11.43 g, 71%). Found: C,73.38; H,8.87; N,4.42. C37H52N2O5 requires C,73.48; H,8.67; N,4.68%.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[OH:20]O>[Cl-].[Na+].O.C[Re](=O)(=O)=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][N+:14]([O-:20])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OO
Reactant: CC(C)(C)c1ccc(-c2ccncc2)cc1
Agent: C[Re](=O)(=O)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1ccc(-c2cc[n+]([O-])cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the mixture of 4-[4-(tert-butyl)phenyl]pyridine (8.7 g, 41 mmol) and methyltrioxorhenium (VII) (Aldrich) (170 mg, 0.7 mmol) in a 100-mL round-bottomed flask was added CH2Cl2 (18 mL). The mixture was then treated with 12 mL of hydrogen peroxide (Aldrich) dropwise. The reaction was stirred at room temperature under nitrogen overnight. Methylene chloride and brine were then added, and the aqueous layer was extracted with CH2Cl2 (40 mL). The organic layer was dried over Na2SO4, concentrated in vacuo to give the title compound as an off-white solid. MS (ESI, pos. ion) m/z: 228 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([CH3:9])[C:7]=1[CH3:8])#[CH:2].[NH2:10][C:11]1[C:19]([C:20]([NH:22][C@H:23]([C:25]2[N:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:33](=[O:41])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][C:31]=3Cl)[N:26]=2)[CH3:24])=[O:21])=[C:14]2[N:15]=[CH:16][CH:17]=[CH:18][N:13]2[N:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C(#N)CC.CC#N.CC#N.Cl[Pd]Cl>[NH2:10][C:11]1[C:19]([C:20]([NH:22][C@H:23]([C:25]2[N:34]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:33](=[O:41])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][C:31]=3[C:2]#[C:1][C:3]3[CH:4]=[N:5][N:6]([CH3:9])[C:7]=3[CH3:8])[N:26]=2)[CH3:24])=[O:21])=[C:14]2[N:15]=[CH:16][CH:17]=[CH:18][N:13]2[N:12]=1
Reactant: C#Cc1cnn(C)c1C
Reactant: C[C@H](NC(=O)c1c(N)nn2cccnc12)c1nc2cccc(Cl)c2c(=O)n1-c1ccccc1
Agent: Cl[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: CCC#N
Solvent: CC#N
Product: Cc1c(C#Cc2cccc3nc([C@H](C)NC(=O)c4c(N)nn5cccnc45)n(-c4ccccc4)c(=O)c23)cnn1C
Temperature: 95 °C
Reaction time: 2 h

Procedure:
Compound 88 was prepared in analogous fashion as compound 21 in example 9 except that 4-ethynyl-1,5-dimethyl-1H-pyrazole was used in place of 4-ethynyl-1-methyl-1H-pyrazole. A suspension of (S)-2-amino-N-(1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (146 mg, 0.317 mmol), Cesium carbonate (198 mg, 0.608 mmol, 2 eq.), Dichlorobis(acetonitrile)palladium (II) (15 mg, 0.058 mmol, 0.2 eq.) and Xphos (87 mg, 0.182, 0.6 eq.) in propionitrile (2 mL) was bubbled with argon for 5 minutes. The mixture was charged with 4-ethynyl-1,5-dimethyl-1H-pyrazole (73 mg, 0.6 mmol, 2 eq.), heated to 95° C. and stirred for 2 hr. The resulting mixture was cooled to RT, partitioned between Ethyl acetate and water. The organic phase was separated, washed with saturated aqueous sodium chloride solution, dried with sodium sulfate and concentrated. The residue was purified with silica gel chromatography using a gradient of DCM and MeOH to afford (S)-2-amino-N-(1-(5-((1,5-dimethyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. ESI-MS m/z: 544.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([C:11]3[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=3[C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:7]=2)[CH:3]=1.[Br:22]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:22][C:5]1[N:6]([C:11]2[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:7]=[C:8]2[C:4]=1[CH:3]=[C:2]([CH3:1])[CH:10]=[CH:9]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccccc1-n1cc2cc(C)ccc2n1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccccc1-n1nc2ccc(C)cc2c1Br
Yield: 80.2 %

Procedure:
Carbon tetrachloride (26 ml) was added to ethyl 2-(5-methyl-2H-indazol-2-yl)benzoate (1.43 g, 5.10 mmol) as obtained in Reference Example 3 and the mixture was stirred. Thereto were added N-bromosuccinimide (0.908 g, 5.10 mmol) and azobisisobutyronitrile (78 mg, 0.48 mmol), and the mixture was refluxed under heating for 3 hours. After cooling, the mixture was filtered, and the cake was washed twice with carbon tetrachloride (5 ml). The filtrate was concentrated, and subjected to flash chromatography on silica gel using a mixed solvent of hexane/ethyl acetate (8:1-3:1), whereby 1.47 g of ethyl 2-(3-bromo-5-methyl-2H-indazol-2-yl)benzoate was obtained.