Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:13])([CH3:12])[C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[CH:14](NC(C)C)(C)[CH3:15].C(I)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:14]([O:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:13])([CH3:12])[C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1)[CH3:15]
Reactant: CC(C)NC(C)C
Reactant: CC(=O)C(C)(C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCI
Product: CCOc1cccc(C(C)(C)C(C)=O)c1

Procedure:
The mixture of 3-(3-hydroxy-phenyl)-3-methyl-butan-2-one (3.4 g, 19.08 mmol), diisopropylamine (16.7 mL, 95.4 mmoL) and ethyl iodide (6.2 mL, 76.32 mmol) in 60 mL of ethanol was heated at refluxed overnight. Thin layer chromatography still showed starting material. Potassium carbonate (9 g) was added, and the mixture was heated at reflux for 12 h. It was concentrated in vacuo, and the residue was taken in ethyl acetate. After being washed with water and brine, the organic layer was dried over anhydrous sodium sulfate. The solids were filtered off, and the filtrate was concentrated to give 3.727 g of 3-(3-ethoxy-phenyl)-3-methyl-butan-2-one as light brown oil. It was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:13])[CH2:5][CH2:6][O:7]2.[CH3:14][Mg]Br.O>C(OCC)C>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([CH3:14])([OH:13])[CH2:5][CH2:6][O:7]2
Reactant: O=C1CCOc2cc(F)cc(F)c21
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: O
Product: CC1(O)CCOc2cc(F)cc(F)c21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.00 g (10.86 mmol) of the compound from Example 170A were dissolved in 40 ml of diethyl ether at 0° C., and 5.4 ml (16.29 mmol) of a 3N solution of methylmagnesium bromide in diethyl ether were slowly added dropwise. Stirring at 0° C. for 1 h was followed by warming to RT, addition of water and diethyl ether to the reaction solution and separation of the phases. The aqueous phase was extracted with diethyl ether, and the combined organic phases were dried over sodium sulfate and filtered, and the solvents were removed in vacuo. The crude product was purified by flash chromatography on silica gel (mobile phase: dichloromethane). 2.03 g (93% of theory) of the title compound were obtained.
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[O:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([SH:30])[CH:27]=[CH:28][CH:29]=1.N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3](=[O:21])[C:2]=1[S:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Br
Reactant: COc1cccc(S)c1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: COc1cccc(SC2=C(O)CC(c3ccccc3)(c3ccccc3)OC2=O)c1

Procedure:
The title compound was prepared as described in General Method 6 from 1.8 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in example AAA), 2.0 mmol of 3-methoxybenzenethiol, and 2.0 mmol of piperidine in 25 mL of dichloromethane. The product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform (m.p. 61°-62° C.). 1H NMR (DMSO-d6) δ3.63 (s, 3H), 3.76 (s, 2H), 5.64 (bd, 1H), 6,42 (s, 1H), 6.54 (d, 1H), 6.74 (t, 1H), 7.32-7.47 (m, 10H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8][CH3:9])=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[N:3]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([S:8][CH3:9])=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:18][CH:17]=2)[N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CSc1c(Cl)nc(-c2ccc(N)cc2)nc1N1CCOCC1
Solvent: ClCCl
Product: CSc1c(Cl)nc(-c2ccc(NS(C)(=O)=O)cc2)nc1N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenylamine (30 mg, 0.091 mmol.), methanesulfonyl chloride (15.5 mg, 0.136 mmol, 1.5 eq.) and CH2Cl2 was added to the reaction vessel and flushed with argon. The reaction mixture was stirred at r.t. for 2 hrs. The reaction mixture was partitioned between CH2Cl2 and NaHCO3 (aq), the organic layer was washed with brine, dried over MgSO4, filtered and evaporated in vacuo. A white solid of 30.3 mg (82.1%) was obtained as the product.
Reaction SMILES: N[C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(#N)C.[BrH:15].N([O-])=O.[Na+]>O>[Br:15][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1c(F)cccc1C(=O)O
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1cccc(F)c1Br
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 78 %

Procedure:
In a 1 L, three necked, round-bottomed flask fitted with a dropping funnel and a thermometer, were charged 20 g (0.13 mol) of 2-amino-3-fluoro-benzoic acid and 160 mL of acetonitrile. After cooling to 0° C., 160 mL of hydrobromic acid (47%) was added dropwise over 10 min. To the resulting solution, 10 g of NaNO2 (0.145 mol) in water (20 mL) was added dropwise over 1 hour. After addition, the reaction mixture was stirred at 0° C. for 5 min, and 21.8 g of Cu(I) Br (0.15 mol) was added portionwise over 30 min. Stirring was continued at 70° C. in an oil bath for 1 hour. After cooling to 0° C., 700 mL of H2O was added and the precipitate was filtered, washed with cold water and dried under vacuum to give an orange solid corresponding to 2-bromo-3-fluoro-benzoic acid (22 g, 78%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[N:17]([O-])=[O:18].[Na+]>C(O)(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:17][OH:18])[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(F)cc1)c1ccncc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(C(=NO)c1ccc(F)cc1)c1ccncc1

Procedure:
2-(4-Fluorophenyl)-1-pyridin-4-ylethanone (0.04 mol/8.6 g) (prepared as described in example 20, steps (a) and (b)) was dissolved in 80 ml of glacial acetic acid. NaNO2 (0.04 mol/2.76 g), dissolved in the smallest amount of H2O possible, was then added dropwise with ice-cooling and stirring. The mixture was then stirred at 0° C. for another 2 h. 500 ml of H2O were then added, and the mixture was stirred at room temperature for another 1 h. The title compound precipitated as a white powder. The precipitate was filtered off, washed with H2O and dried over P2O5 under reduced pressure. Yield: 5.9 g (60%)
Reaction SMILES: [N+](=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[NH:5][C:4]1=[O:13])=[N-].[I:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH:23]([CH3:25])[CH3:24])=[CH2:22])=[CH:17][CH:16]=1>C1C=CC=CC=1.C1COCC1>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][C:4](=[O:13])[C@:3]12[CH2:22][C@:21]1([C:18]1[CH:17]=[CH:16][C:15]([I:14])=[CH:20][CH:19]=1)[CH:23]([CH3:25])[CH3:24]
Reactant: C=C(c1ccc(I)cc1)C(C)C
Reactant: [N-]=[N+]=C1C(=O)Nc2ccc(F)cc21
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CC(C)[C@@]1(c2ccc(I)cc2)C[C@@]12C(=O)Nc1ccc(F)cc12
Temperature: 80 °C
Yield: 105.9 %

Procedure:
The 3-diazo-5-fluoroindolin-2-one (0.177 g, 1 mmol) and Rh(OAc)2 dimer (2.2 mg) were placed into a Schlenk tube under Argon atmosphere, then dissolved in dry benzene (3 mL). The mixture was heated to 80° C. for 10 minutes. The 1-iodo-4-(3-methylbut-1-en-2-yl)benzene (0.544 g) was dissolved in dry THF (2 mL) and added into the mixture in one portion. The mixture was concentrated in vacuo, the residue was purified by flash column chromatography (Petroleum ether: AcOEt=5:1) to give the title compound as white powder (0.446 g, 53%). LC/MS m/e calcd. for C19H17FINO: 421, observed (M+H)+: 422.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[C:4](Cl)[N:3]=1.Cl.[CH:14]12[O:21][CH:18]([CH2:19][CH2:20]1)[CH2:17][NH:16][CH2:15]2.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:16]2[CH2:15][CH:14]3[O:21][CH:18]([CH2:19][CH2:20]3)[CH2:17]2)[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([Cl:8])[N:7]=1
Reactant: C1CC2CNCC1O2
Reactant: O=[N+]([O-])c1c(Cl)nc(Cl)nc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1c(Cl)nc(Cl)nc1N1CC2CCC(C1)O2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2,4,6-Trichloro-5-nitropyrimidine (45, 1.43 g, 6.26 mmoles) was dissolved in dichloromethane and cooled to 0° C. A solution of 8-oxa-3-azabicyclo[3.2.1]octane (2, 0.934 g, 6.26 mmoles) in dichloromethane and triethylamine (0.873 mL, 6.26 mmoles) was slowly added over 1 hour. The solution was allowed to stir at 0° C. for 2 hours, then warmed to room temperature and stirred for an additional 16 hours. The reaction mixture was filtered, the filtrate was concentrated, dissolved in ethyl acetate, washed with 1N hydrochloric acid, saturated sodium bicarbonate, brine, dried, and concentrated to provide 3-(2,6-dichloro-5-nitropyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (46). Yield: 1.53 g (80%). HRMS; [M+H]+ Obs'd=305.0200, [M+H]+ Calc'd=305.0203.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[CH2:12]([N:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCBr
Reactant: O=C1CCCCCN1
Agent: [H-]
Agent: [Na+]
Product: CCCCCCN1CCCCCC1=O
Yield: 85.4 %

Procedure:
Following example 10, from 10.2 g of 50% sodium hydride-mineral oil dispersion (5.1 g NaH, 0.2125 M), 20 g (0.177 M) of azacycloheptan-2-one and 33 g (0.2 M) of 1-bromohexane on 19 hr. reflux was obtained 29.8 g (85.3%) of colorless product; b.p. 122°-128°/0.4 mm.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]2[S:10][CH:11]=[CH:12][C:8]=2[CH:7]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C=O)C>[CH2:15]([O:3][CH2:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]2[S:10][CH:11]=[CH:12][C:8]=2[CH:7]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: OCCc1ccc2sccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(COCCc2ccc3sccc3c2)cc1
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
To a solution of NaH (60% oil dispersion, 2.4 g, 0.06 mol) in DMF (50 ml) heated at 60° C. with stirring under N2 was added dropwise a solution of 5-(2-hydroxyethyl)benzo[b]thiophene (8.9 g, 0.05 mol) in DMF (50 ml). After 1/2 hour, a solution of benzyl bromide (10.3 g, 7.2 ml, d=1.438, 0.06 mol) in DMF (50 ml) was added dropwise. After 15 hours, the solution was poured into H2O and the aqueous phase extracted with ethyl acetate (3X). The organic layers were backwashed with H2O, saturated NaCl, dried, filtered and concentrated to dryness. The residue was chromatographed on silica gel and the product was eluted with 10% (V/V) ethyl acetatehexane to yield 9.7 g (72%) of product. The material was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[CH2:5]([O:7][C:8]([CH2:10][O:11][CH2:12][C:13]([NH:15][NH2:16])=[O:14])=[O:9])[CH3:6]>O1CCCC1>[CH3:1][NH:2][C:3]([NH:16][NH:15][C:13]([CH2:12][O:11][CH2:10][C:8]([O:7][CH2:5][CH3:6])=[O:9])=[O:14])=[S:4]
Reactant: CN=C=S
Reactant: CCOC(=O)COCC(=O)NN
Solvent: C1CCOC1
Product: CCOC(=O)COCC(=O)NNC(=S)NC
Reaction time: 2 h

Procedure:
A solution of methyl isothiocyanate (3.52 g.) in dry tetrahydrofuran (20 ml.) was added during the course of 30 minutes to a suspension of ethoxycarbonylmethoxyacetohydrazide (8.50 g.) in absolute alcohol (50 ml.), and the resulting mixture was stirred for a further period of two hours. The solution was then filtered and the clear filtrate evaporated in vacuo. Trituration of the residue with dry diethyl ether then gave the compound CH3NHCSNHNHCOCH2OCH2COOEt as a white solid material (yield, 8.0 g.).
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][C:4]1[C:5]([F:28])=[CH:6][C:7]([Br:27])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:22])=[C:17](F)[C:18]=3[Cl:20])[C:13](=[O:23])[C:12]([C:24]([OH:26])=[O:25])=[CH:11]2)[CH:9]=1>N1C=CC=CC=1>[NH2:3][C:4]1[C:5]([F:28])=[CH:6][C:7]([Br:27])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:22])=[C:17]([NH:2][CH3:1])[C:18]=3[Cl:20])[C:13](=[O:23])[C:12]([C:24]([OH:26])=[O:25])=[CH:11]2)[CH:9]=1
Reactant: CN
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(Br)cc1F
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3Br)c2c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 40% aqueous solution (60 mg) of methylamine and 1-(5-amino-2-bromo-4-fluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (60 mg) were added to pyridine (2 ml), and the mixture was stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, a mixed liquid of ethanol and diethyl ether was added to the residue, and solids were collected by filtration to obtain the title compound (46 mg) as a pale brown powder.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10](/[C:13](/[C:27]2[NH:28][C:29](=[O:34])[C:30]([Cl:33])=[CH:31][CH:32]=2)=[CH:14]\[CH2:15][N:16]2[C:24](=O)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].O>CO>[C:3]([C:7]1[CH:12]=[CH:11][C:10](/[C:13](/[C:27]2[NH:28][C:29](=[O:34])[C:30]([Cl:33])=[CH:31][CH:32]=2)=[CH:14]\[CH2:15][N:16]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])=[CH:9][CH:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccc(/C(=C\CN2C(=O)c3ccccc3C2=O)c2ccc(Cl)c(=O)[nH]2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1ccc(/C(=C\CN2Cc3ccccc3C2=O)c2ccc(Cl)c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.7 %

Procedure:
Sodium borohydride (52 mg) was added to a suspension of 2-[(2E)-3-(4-tert-butylphenyl)-3-(5-chloro-6-oxo-1,6-dihydropyridin-2-yl)prop-2-en-1-yl]-1H-isoindole-1,3(2H)-dione (50 mg) in methanol (2 mL) under ice-cooling, and the mixture was stirred at room temperature for one hour. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over sodium sulfate and filtered. The solvent was then evaporated under reduced pressure. A solution of the resulting residue in trifluoroacetic acid (2 mL) was stirred under ice-cooling, during which sodium borohydride (50 mg) was added thereto. The mixture was stirred at room temperature for one hour. The reaction solution was ice-cooled, adjusted to a pH of 12 or more with a 1 M sodium hydroxide solution and then extracted with chloroform. The organic layer was dried over sodium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=10:0→9:1) and then powdered with ethyl acetate. The precipitated crystals were collected by filtration and dried to give the title compound as a colorless powder (11 mg, 23%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][NH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(N(CC)CC)C>O1CCOCC1>[Cl:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:10]([CH3:9])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:7]=1
Reactant: CCOC(=O)CNC
Reactant: Clc1ccnc(Cl)n1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(C)c1nccc(Cl)n1

Procedure:
30.0 g (0.20 mol) of 2,4-dichloropyrimidine, 30.9 g (0.20 mol) of ethyl N-methylglycinate and 61.0 g (0.60 mol) of triethylamine in 200 ml of dioxane are stirred at 50° C. for 10 min. The mixture is filtered off with suction and the mother liquor is concentrated to half the original volume. A solid crystallizes out, which is filtered off with suction. The mother liquor is concentrated, the residue is stirred with petroleum ether and the product is filtered off.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH2:6][S:7](Cl)(=[O:9])=[O:8].[CH2:16]([O:18][C:19](=[O:23])[CH2:20][NH:21][CH3:22])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:22][N:21]([CH2:20][C:19]([O:18][CH2:16][CH3:17])=[O:23])[S:7]([CH2:6][C:5]1[CH:11]=[CH:12][CH:13]=[C:3]([C:2]([F:15])([F:14])[F:1])[CH:4]=1)(=[O:9])=[O:8]
Reactant: CCOC(=O)CNC
Reactant: O=S(=O)(Cl)Cc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)CN(C)S(=O)(=O)Cc1cccc(C(F)(F)F)c1
Temperature: 70 °C

Procedure:
In this example, 22 g of 3-trifluoromethylbenzylsulfonyl chloride was added cautiously to a solution containing 27 g of the hydrochloride salt of sarcosine ethyl ester and 12 g of potassium carbonate in 90 ml of water at room temperature. The reaction mixture was heated to about 70° C. and maintained at this temperature for about four hours. The mixture was allowed to cool and then extracted with ethyl ether. The ethyl ether extract was dried over magnesium sulfate, filtered, and evaporated to dryness yielding 9.5 g of the title compound as an off-white solid.
Reaction SMILES: Cl[C:2]1[C:3]([OH:31])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=1[CH:15]=[CH:16][NH:17][C:18]3=[O:23])[C:7]([OH:28])([C:24]([F:27])([F:26])[F:25])[CH2:6][C:5]2([CH3:30])[CH3:29].[C-:32]#[N:33].[Na+]>CN1CCCC1=O.[Ni](Br)Br>[OH:31][C:3]1[C:4]2[C:5]([CH3:30])([CH3:29])[CH2:6][C:7]([OH:28])([C:24]([F:25])([F:27])[F:26])[CH:8]([NH:12][C:13]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:14]=3[CH:15]=[CH:16][NH:17][C:18]4=[O:23])[C:9]=2[CH:10]=[CH:11][C:2]=1[C:32]#[N:33]
Reactant: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3c(=O)[nH]ccc23)c2ccc(Cl)c(O)c21
Reactant: [C-]#N
Agent: Br[Ni]Br
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3c(=O)[nH]ccc23)c2ccc(C#N)c(O)c21
Yield: 22 %

Procedure:
75 mg (0.166 mmol) of 5-(6-chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)-2H-isoquinolin-1-one is dissolved in 1.3 ml of 1-methyl-2-pyrrolidinone and reacted in the microwave with 16.27 mg (0.332 mmol) of sodium cyanide and 36.27 mg (0.166 mmol) of nickel(II) bromide, as described in Example 160. The black reaction mixture is added via a glass fiber filter. After washing with ethyl acetate, the filtrate is also mixed with an additional 60 ml of ethyl acetate. It is shaken with water and with brine. After drying, the solvent is spun off, and the residue is chromatographed on silica gel (amine plate; mobile solvent: methanol/dichloromethane). 16.2 mg (22.1%) of the desired nitrile is isolated.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[N:16]=[CH:17][N:18]([CH3:20])[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.Cl.[CH3:35][O:36][C:37]1[CH:45]=[N:44][C:43]([N:46]2[CH:50]=[N:49][C:48]([CH3:51])=[N:47]2)=[C:42]2[C:38]=1[C:39]([C:52](=[O:56])C(O)=O)=[CH:40][NH:41]2.C(N(CC)CC)(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl>[C:21]1([C:14](=[C:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:52]([C:39]3[C:38]4[C:42](=[C:43]([N:46]5[CH:50]=[N:49][C:48]([CH3:51])=[N:47]5)[N:44]=[CH:45][C:37]=4[O:36][CH3:35])[NH:41][CH:40]=3)=[O:56])[CH2:9][CH2:10]2)[C:15]2[N:16]=[CH:17][N:18]([CH3:20])[CH:19]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)O)c12
Reactant: Cn1cnc(C(=C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2)c1
Agent: CCN(CC)C(C)C
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)N3CCC(=C(c4ccccc4)c4cn(C)cn4)CC3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
To solution of 4-[1-phenyl-1-(1-methylimidazol-4-yl)methylene]piperidine-1-carboxylic acid tert-butyl ester (0.0477 g, 0.0775 mmol) in CH2Cl2 (3 mL) was added TFA (0.3 mL) and the solution was allowed to stir at rt for 30 min. The solvent was then removed in vacuo and the material was dissolved in CHCl3. To this solution was added 4-methoxy-7-(3-methyl-1,2,4-triazol-1-yl)-6-azaindol-3-yl-oxoacetic acid hydrochloride salt (0.0258 g, 0.0764 mmol) and iPrNEt2 (0.024 mL, 1.38 mmol), followed by BOP-Cl (0.0271 g, 0.106 mmol). The mixture was allowed to stir at rt for 2 h and then the solvent was removed in vacuo and the residue was partitioned with H2O-EtOAc. The aqueous phase was re-extracted with EtOAc (×2) and the combined organic layers were washed (H2O, brine), dried (Na2SO4) and evaporated. The resulting residue was purified by preparative HPLC (NH4OAc) to give the title compound (0.0210 g, 50%) as a colorless solid:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:34]=[CH:33][C:30]([CH2:31][OH:32])=[CH:29][CH:28]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[CH:34]=[CH:33][C:30]([CH2:31][OH:32])=[CH:29][CH:28]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: OCc1ccc(Br)cc1
Product: OCc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (2.0 g, 6 mmol) and commercially available 4-bromobenzyl alcohol (1.37 g, 7 mmol) according to general procedure II. Obtained as a light brown solid (575 mg, 22%). MS (ISP) 462.1 [(M+H)+]; mp 200-202° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])[N:8]=1)(=O)=O.CN(C=O)C.CC1(C)C(C)(C)OB([C:41]2[CH:42]=[C:43]([CH2:47][C:48]([O:50]C)=[O:49])[CH:44]=[CH:45][CH:46]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O>[F:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([F:25])[C:18]=1[N:9]1[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=2[C:7]([C:41]2[CH:42]=[C:43]([CH2:47][C:48]([OH:50])=[O:49])[CH:44]=[CH:45][CH:46]=2)=[N:8]1
Reactant: COC(=O)Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2-c1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nccc2c1c(-c1cccc(CC(=O)O)c1)nn2-c1c(F)cccc1F
Temperature: 90 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
To a solution of 1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (600 mg) obtained in Step C of Example 35 in a mixed solvent of DMF (5 mL)/water (0.5 mL) were added methyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (567 mg), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (60 mg) and potassium carbonate (405 mg). The reaction mixture was stirred overnight at 90° C. The reaction mixture was diluted with water, and the aqueous layer was washed with ethyl acetate. The aqueous layer was neutralized with 1M hydrochloric acid at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (205 mg).