Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[C:9]([F:19])[CH:8]=2)[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3]1.Br[C:26]1[S:27][C:28]([CH3:31])=[N:29][N:30]=1.P([O-])([O-])(O)=O.[K+].[K+]>CS(C)=O.O>[CH3:31][C:28]1[S:27][C:26]([N:16]2[CH2:15][CH2:14][CH:13]([C:10]3[CH:11]=[CH:12][C:7]([N:6]4[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3][C:2]4=[O:1])=[CH:8][C:9]=3[F:19])[CH2:18][CH2:17]2)=[N:30][N:29]=1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCNCC3)c(F)c2)C(=O)O1
Reactant: Cc1nnc(Br)s1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(c4nnc(C)s4)CC3)c(F)c2)C(=O)O1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of (S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 20, 550 mg), 2-bromo-5-methyl-1,3,4-thiadiazole (EXAMPLE 87, Step 1, 323 mg) and potassium hydrogenphosphate (571 mg) in dimethyl sulfoxide (16 mL) is stirred under N2 at 100° C. for 2 hrs, cooled to ambient temperature, diluted with water (20 mL) and extracted with methylene chloride (3×20 mL). The combined organic phase is washed with water (20 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated to give the crude product which is then chromatographed on silica gel (230-400 mesh, 45 g), eluting with a gradient of methanol/methylene chloride (2/98-3/97). Pooling and concentration of those fractions with an Rf =0.44 by TLC (methanol/chloroform, 10/90) gives the title compound, mp 193-195° C.
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:13])([CH3:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1.[C:14]([O-:17])(=[O:16])[CH3:15].[K+].O>C(O)(=O)C>[C:14]([O:17][CH2:2][Si:3]([CH3:13])([CH3:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)(=[O:16])[CH3:15]
Reactant: C[Si](C)(CCl)Cc1cccc(F)c1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OC[Si](C)(C)Cc1cccc(F)c1
Yield: 40.2 %

Procedure:
Chloromethyldimethyl-3-fluorobenzylsilane (0.85 g, 3.93 mmol) and potassium acetate (0.83 g, 8.45 mmol) are refluxed in acetic acid (10 ml) for 48 hours. The mixture is then cooled, poured into water (50 ml) and extracted with diethyl ether (50 ml). The organic layer is washed with water, brine, dried over MgSO4 and the solvent is removed in vacuo. Chromatography (silica gel, hexane/ether-80/20 affords the title compound as an oil (0.38 g, 40% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[C:16]3[O:15][CH2:14][CH2:13][C:12]=3[CH:11]=[C:10]([CH2:17][C:18]([OH:20])=[O:19])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Cl[C:24]1C(=O)C(C#N)=C(C#N)C(=O)[C:29]=1Cl.O>O1CCOCC1>[CH2:24]([O:19][C:18](=[O:20])[CH2:17][C:10]1[CH:9]=[C:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:22][CH:21]=2)[C:16]2[O:15][CH:14]=[CH:13][C:12]=2[CH:11]=1)[CH3:29]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: Cc1ccc(C(=O)c2cc(CC(=O)O)cc3c2OCC3)cc1
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)Cc1cc(C(=O)c2ccc(C)cc2)c2occc2c1

Procedure:
7-(4-Methylbenzoyl)-2,3-dihydrobenzofuran-5-ylacetic acid (1.0 g) was dissolved in dioxane (20 ml). To this was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (1.2 g) and the solution heated at reflux for 1 hour. The reaction mixture was added to water and extracted with ethyl acetate, dried with magnesium sulfate and evaporated to dryness. The residue was run on a silica gel column eluting with ethyl acetate/hexane to give ethyl(7-(4-methylbenzoyl)-benzofuran-5-yl)acetate. The acetate was hydrolyzed by the same method set out in Example 3 to give (7-(4-methylbenzoyl)benzofuran-5-yl)acetic acid melting points. This method is especially useful when the 2,3-dihydro starting material contains an alkyl group.
Reaction SMILES: C(O[C:4](=[O:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])C.[CH2:11]([NH2:13])[CH3:12]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].ClCCl.O>[CH2:8]([O:7][C:5](=[O:6])[C:4]([NH:13][CH2:11][CH3:12])=[O:10])[CH3:9]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCN
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCNC(=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 72 h
Yield: 41.3 %

Procedure:
To 135,8 ml (1000 mM) of diethyloxalate and 1 g of aliquat 336, in 1000 ml of dichloromethane, were added 64 ml (1000 mM) of ethylamine at 70% in water. The reaction mixture was stirred at room temperature for 72 h. The reaction mixture was dried over anhydrous sodium sulfate and the solvent was removed under vacuum to give an oil, which was further purified by silica gel column chromatography, using dichloromethane/dimethylketone (95/5) as eluant, to give 59.9 g of ethyl(ethyl amino)(oxo)acetate as an oil.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([C:15]#[N:16])[N:14]=1)[N:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](=[O:24])[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4].[NH2:32][C@@H:33]([C:41]([OH:43])=[O:42])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C[O-].[Na+]>COCCO>[CH2:17]([N:11]1[C:12]2[C:7](=[C:6]([OH:31])[C:5]([C:3]([NH:32][C@H:33]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:41]([OH:43])=[O:42])=[O:4])=[N:14][C:13]=2[C:15]#[N:16])[CH:8]=[C:9]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:10]1=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)c1nc(C#N)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: N#Cc1nc(C(=O)N[C@H](Cc2ccccc2)C(=O)O)c(O)c2cc(-c3ccccc3)c(=O)n(Cc3ccccc3)c12
Temperature: 25 °C
Yield: 100.6 %

Procedure:
A mixture of 1-benzyl-8-cyano-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.073 mmol), D-phenylalanine (241 mg, 1.46 mmol), and NaOMe (59 mg, 1.09 mmol) in 2-methoxyethanol (10 mL) was refluxed for 3 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The residue was chromatographed (5-40% EtOAc/hexanes+2% AcOH) to give 40 mg of the title compound. MS: (+) m/z 545.06 (M+1).
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 (2x), 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: [CH2:1]([N:8]([CH3:30])[C:9]1[C:17]2[S:16][C:15]([NH:18][C:19](=[O:27])[C:20]3[CH:25]=[CH:24][N:23]=[C:22](Br)[CH:21]=3)=[N:14][C:13]=2[C:12]([O:28][CH3:29])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:1]([N:8]([CH3:30])[C:9]1[C:17]2[S:16][C:15]([NH:18][C:19](=[O:27])[C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[CH:21]=3)=[N:14][C:13]=2[C:12]([O:28][CH3:29])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(N(C)Cc2ccccc2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N(C)Cc2ccccc2)c2sc(NC(=O)c3ccnc(N4CCOCC4)c3)nc12

Procedure:
From N-[7-(benzyl-methyl-amino)-4-methoxy-benzothiazol-2-yl]-2-bromo-isonicotinamide with morpholine and cesium carbonate. ES-MS m/e (%): 490 (M+H+, 100).
Reaction SMILES: OCCC1C=CC([NH2:8])=CC=1C(F)(F)F.N1C(C)=CC=CC=1C.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C(Cl)Cl>[CH2:27]([O:26][C:24](=[O:25])[NH2:8])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(CCO)c(C(F)(F)F)c1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 141.9 %

Procedure:
4-(2-Hydroxyethyl)-3-(trifluoromethyl)aniline (408 mg, 2.0 mmol) was dissolved in DCM (10 mL), and 2,6-lutidine (426 mg, 4.0 mmol) and then benzyl chloroformate (678 mg, 4.0 mmol) were dropwise added thereto. The resulting mixture was stirred at room temperature for 1.5 hours. The reaction solution was quenched with a saturated sodium bicarbonate solution, and the organic layer was washed with saturated brine and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (n-hexane:ethyl acetate=3:1) to give 4-(2-hydroxyethyl)-3-(trifluoromethyl)phenyl]carbamic acid benzyl ester (429 mg, 64%) as a light-yellow oil.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:24][CH3:25])[CH2:19][CH2:18][CH2:17]4)=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)[CH3:2].C1(Cl)C(=O)C(Cl)=C(Cl)C(=[O:29])C=1Cl>C(O)C>[CH2:24]([N:20]1[C:21]2[C:16](=[CH:15][C:14]([C:13]([C:9]3[CH:8]=[C:7]4[C:12](=[CH:11][CH:10]=3)[N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6]4)=[O:29])=[CH:23][CH:22]=2)[CH2:17][CH2:18][CH2:19]1)[CH3:25]
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Reactant: CCN1CCCc2cc(Cc3ccc4c(c3)CCCN4CC)ccc21
Solvent: CCO
Product: CCN1CCCc2cc(C(=O)c3ccc4c(c3)CCCN4CC)ccc21
Temperature: 25 °C
Yield: 36.4 %

Procedure:
To 400 ml absolute ethanol was added with stirring 16 g (0.0478 mole) bis-(N-ethyl-1,2,3,4-tetrahydro-6-quinolyl)methane, prepared as described in A, and 23.82 g chloranil. The green mixture was heated to reflux for 1 hour, cooled to room temperature over 1 hour and rotary evaporated to dryness. The residue was taken up in methylene chloride and eluted through neutral Woelm Alumina. A red solid remained on the top of the column. The fractions were rotary evaporated to dryness and the oil taken up in ethanol to yield light yellow crystals which were collected by filtration to give 6.06 g, mp 120°-120.5° C. (36.4% yield). An ultraviolet spectrum in ethanol gave a λmax of 382 nm. ε was 40,500.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]3[N:25]=[N:26][C:27]4[CH:33]=[C:32]([C:34]5[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=5[Cl:41])[CH:31]=[C:30]([CH3:42])[C:28]=4[N:29]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44]>C(Cl)Cl>[OH:49][C:43]([C:45]([F:48])([F:47])[F:46])=[O:44].[Cl:40][C:39]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:41])[C:34]=1[C:32]1[CH:31]=[C:30]([CH3:42])[C:28]2[N:29]=[C:24]([NH:23][C:20]3[CH:19]=[CH:18][C:17]([S:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)(=[O:16])=[O:15])=[CH:22][CH:21]=3)[N:25]=[N:26][C:27]=2[CH:33]=1
Reactant: Cc1cc(-c2c(Cl)cccc2Cl)cc2nnc(Nc3ccc(S(=O)(=O)N4CCN(C(=O)OC(C)(C)C)CC4)cc3)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2c(Cl)cccc2Cl)cc2nnc(Nc3ccc(S(=O)(=O)N4CCNCC4)cc3)nc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.8 %

Procedure:
4-{4-[7-(2,6-dichloro-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamino]-benzenesulfonyl}-piperazine-1-carboxylic acid tert-butyl ester (0.0696 g, 0.111 mmol, 1 equiv) was diluted with DCM (5 mL) and treated with TFA (0.051 mL, 0.664 mmol, 6 equiv). The resulting red solution was stirred at ambient temperature for 6 hours. Additional 6 equivalents of TFA were then added and the reaction was stirred for 12 hours. The solvents were then evaporated and the resulting solids collected and dried to yield a yellow powder (0.062 g, 99% yield). MS (ESI+): m/z=528.9, LC retention time: 2.70 min. 1H NMR (DMSO-d6): δ 2.72 (s, 3H), 3.13 (m, 4H), 3.22 (m, 4H), 7.53 (m, 1H), 7.68 (d, J=8.2 Hz, 2H), 7.81 (d, J=1.6 Hz, 1H), 7.84 (d, J=8.7 Hz, 2 H), 8.20 (d, J=1.7 Hz, 1H), 8.32 (d, J=8.8 Hz, 2H), 8.62 (bs, 2H), 11.53 (s, 1H).
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[CH:10][N:11]=2)=[CH:3][CH:2]=1.[Br:18]N1C(=O)CCC1=O.[O-]S([O-])=O.[Na+].[Na+]>C(#N)C>[C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([C:7]2[S:8][C:9]([Br:18])=[CH:10][N:11]=2)=[CH:3][CH:2]=1
Reactant: c1ccc(-c2ccc(-c3nccs3)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Brc1cnc(-c2ccc(-c3ccccc3)cc2)s1
Temperature: 25 °C
Reaction time: 20 h
Yield: 69 %

Procedure:
To a solution of 2-(biphenyl-4-yl)thiazole (540 mg, 2.28 mmol) in anhydrous acetonitrile (10 mL) was added a solution of N-bromosuccinimide in anhydrous acetonitrile (10 mL). The reaction was stirred for 20 h at room temperature. Subsequently, an aqueous solution of Na2SO3 10% (10 ml) was added and the mixture was stirred for 10 minutes. Then, extracted with ethyl acetate (4×25 mL) and the organic layers were washed with an aqueous saturated solution of NaCl (4×50 ml), dried over Na2SO4, filtered and evaporated under reduced pressure. Flash chromatography of the residue on silica gel (SiO2, hexane:ethyl acetate, 9:1) afforded 500 mg of 2-(biphenyl-4-yl)-5-bromothiazole as a white solid (69% yield). EM (IE): m/z (%): 317; (M+, 100), 315; (M+, 95), 316; (M+, 17.1). HRMS (ESI): (M+H)+: calculated for C15H10BrNS: 315.9717. found: 315.9786.
Reaction SMILES: [C:1]([C:3]1([OH:9])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[CH:2].[F:10][C:11]1[C:12](I)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[F:10][C:11]1[C:12]([C:2]#[C:1][C:3]2([OH:9])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: C#CC1(O)CCOCC1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CC3(O)CCOCC3)c21

Procedure:
Using Method C above, 4-ethynyl-tetrahydro-pyran-4-ol (41.1 mg, 0.33 mmol) (Example 85A) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.13 mmol) (Starting Material 6) using (Ph3P)4Pd (15 mg) and CuI (2.5 mg) as catalyst in DMF (4 mL) and Et3N (4 mL) as solvent at 85° C. for 7 h to yield (Z)-1,3-Dihydro-5-fluoro-4-[(4-hydroxy-tetrahydro-pyran-4-yl)ethynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 36 mg, 75%).
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[CH:5]12[BH:13][CH:9]([CH2:10][CH2:11][CH2:12]1)[CH2:8][CH2:7][CH2:6]2>C1COCC1>[CH3:4][CH:2]([CH3:3])[CH2:1][B:13]1[CH:5]2[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:8][CH2:7][CH2:6]2
Reactant: C=C(C)C
Reactant: B1C2CCCC1CCC2
Solvent: C1CCOC1
Product: CC(C)CB1C2CCCC1CCC2
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of isobutylene (4.40 g, 78.45 mmol) in 11 ml THF at -78° C., 9-Borabicyclo[3.3.1]nonane (9-BBN) (0.5 M in THF, 157 ml, 78.45 mmol) was added. The mixture was stirred at -78° C. for 3 hours, and then warmed to room temperature and stirred overnight to form 9-(2-Methylpropyl)-9-borabicyclo[3.3.1]nonane (9-isobutyl BBN). In a separate flask, to a solution of 3-bromobenzylalcohol (13.34 g, 71.32 mmol) in 36 ml THF, tetrakis(triphenylphosphine)palladium(0) (2.47 g, 2.14 mmol) and 60 ml 3M NaOH were added. The 9-isobutyl BBN prepared above was then transferred into the flask under argon and the mixture was refluxed for 21 hours. The mixture was cooled with an external ice bath and 18 ml 30% hydrogen peroxide was added. The mixture was stirred for 30 minutes, concentrated to about 100 ml and partitioned between 200 ml each of water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (2×100 ml) and the combined organic extracts were washed with 60 ml brine, dried and concentrated. The residue was chromatographed on silica gel using 9:1 hexane/ethyl acetate to afford compound A (8.16 g, 70%) as a liquid.
Reaction SMILES: CNC1N=C(C2C=CC=CN=2)C=C(C2C=NC=C(C#CC3N(C)C=NC=3)C=2)C=1.Br[C:30]1[CH:31]=[C:32]([C:36]2[CH:41]=[C:40]([NH:42][CH:43]3[CH2:45][CH2:44]3)[N:39]=[C:38]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=3)[CH:37]=2)[CH:33]=[N:34][CH:35]=1.[C:52]([C:54]1([OH:61])[CH2:59][CH2:58][N:57]([CH3:60])[CH2:56][CH2:55]1)#[CH:53]>>[CH:43]1([NH:42][C:40]2[N:39]=[C:38]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=3)[CH:37]=[C:36]([C:32]3[CH:33]=[N:34][CH:35]=[C:30]([C:53]#[C:52][C:54]4([OH:61])[CH2:59][CH2:58][N:57]([CH3:60])[CH2:56][CH2:55]4)[CH:31]=3)[CH:41]=2)[CH2:45][CH2:44]1
Reactant: C#CC1(O)CCN(C)CC1
Reactant: Brc1cncc(-c2cc(NC3CC3)nc(-c3ccccn3)c2)c1
Agent: CNc1cc(-c2cncc(C#Cc3cncn3C)c2)cc(-c2ccccn2)n1
Product: CN1CCC(O)(C#Cc2cncc(-c3cc(NC4CC4)nc(-c4ccccn4)c3)c2)CC1

Procedure:
is prepared analogously to Methyl-[5″-(3-methyl-3H-imidazol-4-ylethynyl)-[2,2′;4′,3″]terpyridin-6′-yl]-amine (Example 2.182) by replacing (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-methyl-amine (Example 2.1; step1) with (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-cyclopropyl-amine (Example 1.26) and by replacing 1-methyl-5-((trimethylsilyl)ethynyl)-1H-imidazole with 4-ethynyl-1-methylpiperidin-4-ol.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([Cl:11])[N:3]=1.[CH:12]12[O:17][CH:16]1[CH2:15][CH:14]=[CH:13]2>CS(C)=O.O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:13]2[CH2:12][C@H:16]([OH:17])[CH:15]=[CH:14]2)=[C:4]([Cl:11])[N:3]=1
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Reactant: C1=CC2OC2C1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](O)C3)c2n1
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
To a stirred solution of 2-amino-6-chloro-9H-purine (4.0 g, 23.7 mmol) in dry dimethylsulfoxide (40 mL) at room temperature under N2 is added tetrakis(triphenylphosphine)palladium(O) (0.27 g, 0.23 mmol) and the mixture is stirred for 2 minutes. The solution is cooled to 0° C. and a solution of 6-oxa-bicyclo[3.1.0]hex-2-ene (2.1 g, 25.6 mmol) in dry tetrahydrofuran (20 mL) is added over 15 minutes. The resulting yellow solution is allowed to warm to ambient temperature (about 15°-30° C.) over 3 hours and stirred overnight (about 16 h). The clear, yellow solution is evaporated to a viscous oil which is taken up in dichloromethane (50 mL) and filtered through a small pad of Celite (trademark of Manville Products Corp. for infusorial earth filter aid). The solvent is evaporated and the residue is purified by silica gel chromatography using i) ethyl acetate followed by ii) 10:1 ethyl acetate:methanol as eluent to give cis-(±)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclo-penten-1-ol as a white solid, 5.14 g (86%). M.pt. 160°-162° C. 1H nmr: δ7.83 (s, 1H), 6.34 (dt, J1 =5.5 Hz, J2 =2 Hz, 1H), 5.85 (dd, J1 =5.5 Hz, 1H), 5.34 (d, J=10 Hz, 1H), 5.26 (dq, J1 =9 Hz, J2 =2 Hz, 1H), 5.12 (br s, 2H), 4.85 (br t, J=9 Hz, 1H), 2.97 (ddd, J1 =15 Hz, J2 =9 Hz, J3 =7 Hz, 1H), 2.13 (br d, J=15 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]([CH2:17][CH:18]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=1)[CH2:19][CH2:20]S(C)(=O)=O)[C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1.I.[NH:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:35]1[C:43]([CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)=[O:44]>>[CH3:1][N:2]([CH2:17][CH:18]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=1)[CH2:19][CH2:20][N:48]1[CH2:49][CH2:50][CH:45]([C:43]([C:35]2[NH:34][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[N:36]=2)=[O:44])[CH2:46][CH2:47]1)[C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1
Reactant: COc1cc(C(=O)N(C)CC(CCS(C)(=O)=O)c2ccc(C)c(C)c2)cc(OC)c1OC
Reactant: O=C(c1nc2ccccc2[nH]1)C1CCNCC1
Agent: I
Product: COc1cc(C(=O)N(C)CC(CCN2CCC(C(=O)c3nc4ccccc4[nH]3)CC2)c2ccc(C)c(C)c2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 1.7 using N-methyl-N-(2-(3,4-dimethylphenyl)-4-methanesulfonylbutyl)-3,4,5-trimethoxybenzamide and 4-(1H-benzimidazole-2-carbonyl)piperidine hydriodic acid salt to give the title compound.
Reaction SMILES: [NH2:1][C:2]([CH3:25])([CH3:24])[C:3]([NH:5][C:6]1[S:7][C:8]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:10]=1)=[O:4].[CH:26]1([CH2:31][C:32](Cl)=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27]1.C(N(CC)CC)C>C(Cl)Cl>[CH:26]1([CH2:31][C:32]([NH:1][C:2]([CH3:25])([CH3:24])[C:3]([NH:5][C:6]2[S:7][C:8]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)=[O:4])=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CC(C)(N)C(=O)Nc1nc(-c2ccc(F)cc2)c(N2CCOCC2)s1
Reactant: O=C(Cl)CC1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(NC(=O)CC1CCCC1)C(=O)Nc1nc(-c2ccc(F)cc2)c(N2CCOCC2)s1

Procedure:
2-Amino-N-[4-(4-fluoro-phenyl)-5-morpholin-4-yl-thiazol-2-yl]-2-methyl-propionamide (1 eq), cyclopentyl acetyl chloride (1.05 eq) and triethyl amine (3 eq) were stirred as a solution in DCM (5 mL). Desired product was isolated from reaction mixture by silica gel chromatography. LCMS Method 10 Rt=1.48 (M+1=475.1, M−1=473.1), HRMS; expected=474.2101, found=474.2116. 1H NMR (400 MHz, DMSO-D6) 1.07-1.18 (m, 2H) 1.38 (s, 5H) 1.42-1.51 (m, 2H) 1.52-1.60 (m, 2H) 1.62-1.73 (m, 2H) 2.11 (s, 3H) 2.78-2.88 (m, 4H) 3.69-3.78 (m, 4H) 7.23 (t, J=8.91 Hz, 2H) 8.01 (s, 1H) 8.13 (dd. J=8.59, 5.81 Hz, 2H) 11.45 (s, 1H).