Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[N:4][C:5]([F:10])=[C:6]([F:9])[C:7]=1F.[F:12][C:13]([F:17])([F:16])[CH2:14][O-:15].[Na+].C(O)C(F)(F)F.[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[C:3]([F:11])=[N:4][C:5]([F:10])=[C:6]([F:9])[C:7]=1[O:15][CH2:14][C:13]([F:17])([F:16])[F:12]
Reactant: Fc1nc(F)c(Cl)c(F)c1F
Reactant: [O-]CC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: OCC(F)(F)F
Solvent: C1CCOC1
Product: Fc1nc(F)c(Cl)c(OCC(F)(F)F)c1F
Temperature: -78 °C
Reaction time: 18 h
Yield: 63.3 %

Procedure:
3-Chloro-2,4,5,6-tetrafluoropyridine (18.0 g, 97.0 mmol) was dissolved in anhydrous THF (100 mL) under an N2 atmosphere and the resulting solution cooled to −78° C. To the cold solution was slowly added a solution of sodium 2,2,2-trifluoroethoxide (97 mmol), prepared from trifluoroethanol (7.1 mL, 97.0 mmol) and NaH (3.88 g, 97.0 mmol, 60% dispersion in mineral oil), in anhydrous THF (100 mL). The resulting mixture was slowly warmed to ambient temperature. After 18 h at ambient temperature a GC analysis indicates all the starting material was consumed. The volatiles were evaporated and the residue dissolved in CH2Cl2 (200 mL). The organics were washed with H2O (3×100 mL), dried (MgSO4), filtered and concentrated to give the crude product as a yellow oil. The yellow oil was distilled at reduced pressure to afford 3-chloro-2,5,6-trifluoro-4-(2,2,2-trifluoroethoxy)pyridine as a clear oil (16.3 g, 63% yield): by 48° C. (ca 0.2 mm Hg); 1H NMR (CDCl3) δ 4.81-4.78 (dq, J=1.6, 7.7 Hz); GC-MS (EI, 70 eV) m/z (% relative intensity) 267 (33), 265 (100), 248 (5), 246 (16), 198 (22), 196 (60).
Reaction SMILES: [Cl:1][C:2]1[NH:11][C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1.[CH3:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br.C(Br)C1C=CC=CC=1>>[Cl:1][C:2]1[N:11]([CH2:15][C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[CH3:18])[C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1
Reactant: Cn1c(=O)c2[nH]c(Cl)nc2n(C)c1=O
Reactant: Cc1ccccc1CBr
Agent: BrCc1ccccc1
Product: Cc1ccccc1Cn1c(Cl)nc2c1c(=O)n(C)c(=O)n2C
Reaction time: 24 h

Procedure:
From 8-Chorotheophylline (10 g, 47 mmol) and 2-methylbenzyl bromide (13.6 ml, 103 mmol). The benzyl bromide was added in two portions. First half at reaction start as described in general procedure (E), and the other half after 24 hours as the reaction had not completed.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([O:12][CH3:13])=[CH:7]2.[C:14]1([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([OH:37])=[N:35][CH:36]=3)=[N:22][N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([O:37][C:34]3[N:35]=[CH:36][C:31]([NH:30][C:23]4[C:24]5[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:20]([C:14]5[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=5)=[N:21][N:22]=4)=[CH:32][CH:33]=3)=[CH:3][CH:4]=[N:5]2)=[N:10][CH:9]=1
Reactant: Oc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cn1
Reactant: COc1cnc2c(Cl)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COc1cnc2c(Oc3ccc(Nc4nnc(-c5ccccc5)c5ccccc45)cn3)ccnc2c1
Temperature: 130 °C
Reaction time: 3.5 h

Procedure:
A pyrex reaction tube was charged with 8-chloro-3-methoxy-1,5-naphthyridine (50 mg, 0.26 mmol), 5-(4-phenylphthalazin-1-ylamino)pyridin-2-ol (80 mg, 0.26 mmol), cesium carbonate (249 mg, 0.76 mmol) and DMSO (2 mL). The tube was sealed and the reaction mixture was heated to 130° C. After 3.5 h, an aliquot was analyzed by LCMS, and the desired product was determined to be the major peak. The reaction mixture was diluted with DMSO and purified by Gilson HPLC {5-65% (0.1% TFA in CH3CN) in H2O over 20 min}. The product-containing fractions were combined, basified by addition of aq. NaHCO3 and extracted with DCM. The organic portion was dried with Na2SO4, filtered, and concentrated to afford material that was further purified by silica gel chromatography, 90/10/1 CH2Cl2/MeOH/NH4OH. This provided N-(6-(7-methoxy-1,5-naphthyridin-4-yloxy)pyridin-3-yl)-4-phenylphthalazin-1-amine as pure material. MS [M+H]=473.0@1.48 minutes. Calc'd for C28H20N6O2: 472.5.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[Cl:6][C:7]1[C:8]([O:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:9]([CH:11]=[CH:12][C:13]=1[O:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[NH2:10]>FC(F)(F)C(O)=O>[Cl:6][C:7]1[C:8]([O:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:9]([C:11]([N+:1]([O-:4])=[O:2])=[CH:12][C:13]=1[O:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[NH2:10]
Reactant: O=[N+]([O-])[O-]
Reactant: Nc1ccc(Oc2cccnc2)c(Cl)c1Oc1cccnc1
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1c([N+](=O)[O-])cc(Oc2cccnc2)c(Cl)c1Oc1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
315 mg of potassium nitrate was added to a trifluoroacetic acid (20 ml) solution of 891 mg of 3-chloro-2,4-bis(pyridin-3-yloxy)aniline, and the reaction liquid was stirred overnight at room temperature, and then the solvent was evaporated away under reduced pressure. The residue was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate and saturated saline in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified with silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/1 to ethyl acetate) to obtain the entitled compound as an orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[I:11]N1C(=O)CCC1=O>ClC(Cl)C.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]ncc2c1
Reactant: O=C1CCC(=O)N1I
Solvent: C1CCOC1
Solvent: CC(Cl)Cl
Product: Brc1cnc2[nH]nc(I)c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.1 %

Procedure:
5-bromo-1H-pyrazolo[3,4-b]pyridine (3.00 g, 15.2 mmol) and N-iodosuccinimide (3.60 g, 16.0 mmol) were dissolved in anhydrous dichloroethane (100 mL). The resulting mixture was stirred under reflux conditions for 6 h, cooled to room temperature and diluted with THF (300 mL). The resulting solution was washed with a saturated aqueous solution of sodium thiosulfate (100 mL) and brine, then dried over magnesium sulfate, filtered and concentrated. The residue was titurated with a 1:1 mixture of dichloromethane and ether and then ether before being dried in vacuum to afford 5-bromo-3-iodo-1H-pyrazolo[3,4-b]pyridine (3.795 g, 77% yield) as a beige-brown solid. 1H-NMR (500 MHz, d6-DMSO) δ 14.31 (s, 1H), 8.65 (d, 1H), 8.20 (d, 1H). MS: m/z 323, 325 [MH+].
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([NH:14][NH2:15])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:16]1(C)[CH:21]=CC(S(O)(=O)=O)=C[CH:17]=1>CC(C)=O>[OH:1][C:2]1[C:3]([C:12]([NH:14][N:15]=[C:16]([CH3:21])[CH3:17])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: NNC(=O)c1cc2ccccc2cc1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC(C)=NNC(=O)c1cc2ccccc2cc1O
Temperature: 20 °C

Procedure:
A four neck flask (3 liters) equipped with a thermometer, a reflux condenser and a stirrer was charged with 121.2 g (0.6 mol) of 3-hydroxy-2-naphthohydrazide, 1.14 g (0.006 mol) of p-toluenesulfonic acid and 2 liters of acetone and then heated under reflux for 5 hours. The reaction liquid was cooled down to 20° C. or lower, and then crystal was filtered off and dried under reduced pressure, whereby the intended compound (slightly yellow crystal) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cccc(OCc2ccccc2)c1
Reaction time: 16 h

Procedure:
To a stirred solution of Ethyl 2-(3-hydroxyphenyl)acetate (3 g, 16.6 mmol) in DMF (25 ml) was added potassium carbonate (2.99 g, 21.6 mmol) at room temperature followed by drop wise addition of benzyl bromide (3.13 g, 18.3 mmol). The reaction mixture was stirred for 16 hours and taken in ethyl acetate, washed with water (2×) and brine. The organic layer was dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (hex:ethyl acetate 4:1) to give the title compound.
Reaction SMILES: Cl[CH2:2][C:3](=[N:17][OH:18])[CH2:4][O:5][C:6]1[C:10]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:9][S:8][N:7]=1.[CH:19]([NH2:22])([CH3:21])[CH3:20]>C1COCC1>[CH:19]([NH:22][CH2:2][C:3](=[N:17][OH:18])[CH2:4][O:5][C:6]1[C:10]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:9][S:8][N:7]=1)([CH3:21])[CH3:20]
Reactant: ON=C(CCl)COc1nsnc1N1CCOCC1
Reactant: CC(C)N
Solvent: C1CCOC1
Product: CC(C)NCC(COc1nsnc1N1CCOCC1)=NO
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
In a 200 mL round-bottomed flask were placed 3-chloro-1-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy]-2-propanone oxime 4b (3.53 g, 12.1 mmole), isopropylamine (3.56 g, 60.3 mmole), and THF (71 mL). The mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated in vacuo at room temperature. The residue was triturated with isopropyl ether and precipitated crystals were filtered with suction. The crystals were dissolved in dil. HCl solution. To the solution were added ether and NaHCO3 in small portions under vigorous stirring conditions. The organic layer was washed with water and dried over anyydrous MgSO4, and concentrated in vacuo. Yield: 0.42 g (11.6%) from isopropyl ether.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.Cl.[NH2:14][CH2:15][CH2:16][C:17]1[S:18][CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:21]=1.[OH-].[NH4+]>O>[F:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[NH:14][CH2:15][CH2:16][C:17]1[S:18][CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:21]=1
Reactant: Fc1cccc2c(Cl)ccnc12
Reactant: NCCc1nc(-c2ccccc2)cs1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Fc1cccc2c(NCCc3nc(-c4ccccc4)cs3)ccnc12
Yield: 21.3 %

Procedure:
To 1.0 g of 4-chloro-8-fluoroquinoline was added 2.6 g of 2-β-aminoethyl-4-phenylthiazole monohydrochloride. The mixture was stirred under nitrogen and heated to 170°-175° C. for one hour. The mixture was then cooled and 250 mL of a 50:50 mixture of ammonium hydroxide and water was added. The product was extracted into CH2Cl2, which was then concentrated to dryness. Recrystallizing from pentane/CH2Cl2 gave 0.410 g of the title product. Yield 21.6%. M.P. 134°-135° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([N:13]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:14](=O)[N:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH3:35].CO>C(OCC)C>[C:7]1([N:13]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:14]([N:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[NH:35])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N
Reactant: O=C(N(c1ccccc1)c1ccccc1)N(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: CCOCC
Product: N=C(N(c1ccccc1)c1ccccc1)N(c1ccccc1)c1ccccc1
Reaction time: 48 h

Procedure:
A solution of diphenylamine (3.05 g, 18 mmol) and triethylamine (6 mL, 43 mmol) in THF (62 mL) was added dropwise to a stirred solution of triphosgene (1.99 g, 6.7 mmol) in THF (37 mL) at room temperature. The reaction mixture was heated to reflux overnight. Then, a solution of diphenylamine (3.1 g, 18 mmol) and triethylamine (5.8 mL, 42 mmol) in THF (37 mL) was added. The reaction mixture was stirred overnight at reflux temperature. The reaction mixture was filtered and the filtrate was evaporated to dryness, yielding tetraphenylurea as a yellow solid. Yield: 6.0 g (91%). Oxalyl chloride (1.8 mL, 21 mmol) was added to a stirred solution of the urea (6.0 g, 16 mmol) in diethyl ether (65 mL). The reaction mixture was evaporated to dryness after stirring for 2 days at reflux. A solution of ammonia in methanol (5 mL, 35 mmol, 7 M) was added. The reaction mixture was heated to reflux overnight and evaporated to dryness. The product was neutralized and purified from ammonium chloride by several treatments with aqueous sodium hydroxide solutions. The organic layer was extracted and dried over sodium sulfate. Crystallization from diethyl ether at low temperature yielded the desired guanidine as a white solid. Yield: 2.0 g (33%). 13C NMR (CDCl3, 75 MHz): δ 121.4, 126.7, 128.6, 140.3, 164.5 ppm.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8](B(O)O)=[CH:9][C:4]=2[CH2:3][CH2:2]1.I[C:14]1[C:22]2[C:17](=[N:18][CH:19]=[N:20][C:21]=2[NH2:23])[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[N:20][C:21]=4[NH2:23])[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: OB(O)c1ccc2c(c1)CCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2ccc3c(c2)CCO3)c2c(N)ncnc21
Temperature: 80 °C
Yield: 53.2 %

Procedure:
A solution of 2,3-dihydro-1-benzofuran-5-ylboronic acid (38 mg, 0.23 mmol) in EtOH (1.65 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.1 mmol) in DME (6 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (0.95 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA95 (15.7 mg, 59% yield). ESI-MS (M+H)+ m/z calcd 296.1, found 296.1.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC#N>[CH2:17]([O:9][C:8]([CH:5]1[CH2:6][CH2:7][CH:2]([N:1]([CH2:8][C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:3][CH2:4]1)=[O:10])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: NC1CCC(C(=O)O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(OCc1ccccc1)C1CCC(N(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
4-Amino-cyclohexanecarboxylic acid (16 g, 0.11 mol) was treated with K2CO3 (46.8 g) in MeCN (225 mL) at 80° C. under Ar. Benzyl bromide (46.6 mL) in MeCN (140 mL) was then added dropwise and stirred at 80° C. for approximately 20 hours and allowed to cool to RT, to yield 4-dibenzylamino-cyclohexanecarboxylic acid benzyl ester (55.04 g) after workup.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[N:6][C:5]=2[C:4]([CH2:23][CH2:24][CH3:25])=[N:3]1.Cl.[OH-:27].[Na+]>>[CH3:1][N:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([OH:27])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[N:6][C:5]=2[C:4]([CH2:23][CH2:24][CH3:25])=[N:3]1
Reactant: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(S(=O)(=O)Cl)cc3)nc12
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(S(=O)(=O)O)cc3)nc12

Procedure:
A solution of 4-[(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)methyl]-1-benzenesulfonyl chloride (250 mg, 0.00065 mol) in 1N aqueous sodium hydroxide solution (3 ml) was stirred at room temperature for 2 hours. The reaction was acidified to pH1 with 2N aqueous hydrochloric acid and the resulting crystals filtered, washed with water, and dried by air suction, to yield the title compound (178 mg), m.p.>350° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH2:17])[C:14]([NH2:18])=[C:13]([NH2:19])[N:12]=1.[F:20][C:21]([F:28])([F:27])[C:22](=O)[C:23]([O-])=[O:24]>>[NH2:17][C:15]1[C:14]2[N:18]=[C:22]([C:21]([F:28])([F:27])[F:20])[C:23](=[O:24])[NH:19][C:13]=2[N:12]=[C:11]([S:10][CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[N:16]=1
Reactant: O=C([O-])C(=O)C(F)(F)F
Reactant: Nc1nc(SCc2cccc(F)c2F)nc(N)c1N
Product: Nc1nc(SCc2cccc(F)c2F)nc2[nH]c(=O)c(C(F)(F)F)nc12

Procedure:
The sub-titled compound was prepared from the product of Example 2, step (c) (5 g) and trifluoropyruvate (10 ml) using the method of Example 2, step (d).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[F:22][C:23]([F:32])([F:33])[C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:1][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:11][CH:10]=3)=[CH:5][CH:4]=2)=[CH:26][CH:25]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccc(CN)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)c1ccc(-c2ccc(CNCc3ccc(C(F)(F)F)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 43 %

Procedure:
To a solution of tert-butyl 4′-(aminomethyl)-1,1′-biphenyl-4-carboxylate (2.0 g) and 4-(trifluormethyl)-benzaldehyde (0.88 mL) in DCE (40 mL) was added at once sodium triacetoxyborohydride (1.904 g). The resulting mixture was stirred for 14 h at rt. Water (50 mL) was added and the mixture extracted with DCM (3×). The combined organic layers were washed with water (50 mL), then dried over MgSO4, evaporated off to give a yellow oil. This crude was purified by flash chromatography (c-Hex/AcOEt 4/1) to give the title compound as a white powder (1.30 g, 43%). M+(LC/MS(ESI)): 442.02
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][C@@H:17]2[C@@:13]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([CH2:14][C:15](=[CH2:19])[CH2:16]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:30])=[N-]>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][C@@H:17]2[C@@:13]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([CH2:14][C:15]3([CH2:16]2)[CH2:30][CH2:19]3)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=[N+]=[N-]
Reactant: C=C1C[C@@H]2CN(C(=O)OCc3ccccc3)C[C@]2(NC(=O)OC(C)(C)C)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@]12CN(C(=O)OCc3ccccc3)C[C@H]1CC1(CC1)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Palladium acetate (5.26 mg, 0.0234 mmol) was added to (1S,5R)-3-benzyloxycarbonyl-1-tert-butoxycarbonylamino-7-methylene-3-azabicyclo[3.3.0]octane (175 mg, 0.469 mmol) in diethyl ether (4.69 ml) in an open system under ice-cooling. The previously prepared solution of diazomethane in diethyl ether (20 ml) was slowly added to this solution under ice-cooling, and the mixture was stirred at room temperature for 16 hours. After filtration through Celite, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→95:5→90:10→88:12→87:13→86:14→85:15→83:17→80:20→75:25) to give 138 mg of the title compound as a transparent oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]([NH2:9])=[N:7][CH:8]=1)#[CH:2].I[C:11]1[CH:12]=[C:13]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)=[O:15].CC#N>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CCN(CC)CC>[NH2:9][C:6]1[N:7]=[CH:8][C:3]([C:1]#[C:2][C:28]2[CH:27]=[C:13]([CH:12]=[CH:11][C:29]=2[CH3:30])[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=2)=[O:15])=[CH:4][N:5]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1I
Reactant: C#Cc1cnc(N)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1C#Cc1cnc(N)nc1
Temperature: 90 °C

Procedure:
To a sealable tube containing 5-ethynylpyrimidin-2-amine (172 mg, 1.44 mmol), PdCl2(PPh3)2 (25 mg, 0.036 mmol), 3-iodo-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide (292 mg, 0.72 mmol) was added MeCN (10 mL) and Et3N (3 mL) followed by CuI (6.8 mg, 0.036 mmol). The tube was sealed and heated at 90° C. for 1 h. The reaction was allowed to cool to room temperature and concentrated under reduced pressure. The resulting brown solid was reconstituted in MeOH:CH2Cl2 (1:1, 10 mL) and silica gel was added and reconcentrated. The silica-gel combined crude mixture was purified via automated flash chromatography (silica gel, 0 to 5% MeOH in CH2Cl2, gradient elution) to afford 3-(2-(2-aminopyrimidin-5-yl)ethynyl)-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide. MS m/z=397 [M+H]+. Calc'd for C21H15F3N4O: 396
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.[S:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O>>[CH3:18][O:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:9]=1[CH:2]1[N:1]([CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([C:20]3[S:19][CH:23]=[CH:22][N:21]=3)[CH:25]=2)[C:5](=[O:7])[CH2:4][CH2:3]1
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-c2nccs2)c1
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1cccc(-c2nccs2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate with commercially available 3-(thiazol-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.79 min.; [M+H]+: 395.12 g/mol.
Reaction SMILES: [OH-].[Na+:2].[CH:3]1([P:9]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([OH:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.O>CO>[CH:26]1([P:9]([CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)[CH:10]2[CH2:11][CH2:12][CH:13]([C:16]3[CH:17]=[CH:18][C:19]([S:22]([O-:25])(=[O:24])=[O:23])=[CH:20][CH:21]=3)[CH2:14][CH2:15]2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1.[Na+:2]
Reactant: O=S(=O)(O)c1ccc(C2CCC(P(C3CCCCC3)C3CCCCC3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=S(=O)([O-])c1ccc(C2CCC(P(C3CCCCC3)C3CCCCC3)CC2)cc1

Procedure:
Sodium hydroxide (1.82 g; 45.5 mol.) is dissolved in 50 mL of methanol and added dropwise under nitrogen to 4-[4-(dicyclohexylphosphino)-cyclohexyl]benzenesulfonic acid (19.86 g; 45.5 mmol.) in 200 mL of methanol. The pH of the resulting system upon mixing with water is about 9.4. The mixture in methanol is filtered, the solvent is evaporated and the residue is dried in vacuum to constant weight. Yield of sodium 4-[4-(dicyclohexyl-phosphino)cyclohexyl]benzenesulfonate, Cy2PC6H10C6H4SO3Na, is 20.4 g (98%). 31P{1H} NMR CD3OD, ppm): −1.28. 1H NMR (δ CD3OD, ppm): 1.2-2.2 (m, 31H, cyclohexyl), 2.74 (m, 1H, PhCH), 7.34 and 7.74 (dd, J=8.2 Hz, 4H, aromatic).