Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[CH2:11]([NH2:14])[C:12]#[CH:13].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][NH:14][CH2:11][C:12]#[CH:13]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: C#CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: C#CCNCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 59.6 %

Procedure:
To a solution of 3,4-difluorobenzaldehyde (5 g, 35.2 mmol) in 200 mL dichloroethane was added mono-propargyl amine (4.85 mL, 70.7 mmol, 2 eq.) followed by Na(OAc)3BH (9 g, 42.5 mmol) and the mixture was stirred for 2 days at room temperature. The solution was diluted with 100 mL of dichloromethane, washed with 2×100 mL aq. NaHCO3, 100 mL brine, dried over Na2SO4, filtered and concentrated. The crude product was chromatographed with 20:80 ethyl acetate-hexanes to provide 3.8 g of (3,4-difluoro-benzyl)-prop-2-ynyl-amine as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)=[C:4]([F:13])[CH:3]=1.IC1C=C(O)C=CC=1.[CH:22]1([C:27]([OH:44])([C:38]#[C:39][Si](C)(C)C)[CH2:28][C:29]2[O:34][C:33]([CH3:36])([CH3:35])[O:32][C:31](=[O:37])[CH:30]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([C:27]([OH:44])([CH2:28][C:29]2[O:34][C:33]([CH3:35])([CH3:36])[O:32][C:31](=[O:37])[CH:30]=2)[C:38]#[C:39][C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:11]#[N:12])[CH2:10][CH2:9]3)=[C:4]([F:13])[CH:3]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC1(C)OC(=O)C=C(CC(O)(C#C[Si](C)(C)C)C2CCCC2)O1
Reactant: N#CC1(c2ccc(Br)cc2F)CC1
Agent: Oc1cccc(I)c1
Product: CC1(C)OC(=O)C=C(CC(O)(C#Cc2ccc(C3(C#N)CC3)c(F)c2)C2CCCC2)O1

Procedure:
The desired product was prepared analogously to example F(7), tep 5, substituting 1-(4-bromo-2-fluoro-phenyl)-cyclopropanecarbonitrile (0.96 g, 4.0 mmol), from Step 2 above in place of 3-iodophenol, and 6-(2-cyclopentyl-2-hydroxy-but-3-ynyl)-2,2-dimethyl-[1,3]dioxin-4-one (1.06 g, 4.0 mmol; from Step 4 above) in place of 6-but-3-ynyl-3-chloro-6-cyclopentyl-dihydro-pyran-2,4-dione. Yield: 1.241 g, 73%. MS (ESI): 422 (M−H).
Reaction SMILES: [CH:1]([O-:3])=O.[Na+].Br[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[F:16])[N:12]=[CH:11][CH:10]=[CH:9]2>C(#N)C.CS(C)=O.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>[F:16][C:15]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[CH:1]=[O:3]
Reactant: Fc1cc2ncccc2cc1Br
Reactant: O=C[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC#N
Product: O=Cc1cc2cccnc2cc1F
Temperature: 120 °C
Yield: 10.4 %

Procedure:
To a suspension of Pd(PPh3)4 (1.27 g, 1.1 mmol) and sodium formate (13.8 g, 132 mmol, 6 e.q.) in acetonitrile (30 mL) was added a solution of 6-bromo-7-fluoro quinoline (5 g, 22 mmol) in DMSO (30 mL). The reaction mixture was heated at 120° C. under a CO atmosphere (1 MPa) for 4 h, cooled to rt and concentrated under reduced pressure. The residue was partitioned between water (100 mL) and ethyl acetate (150 mL). The organic layer was separated, washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The reside was purified by column choromatography, eluting with petroleum:ethyl acetate=10:1˜3:1 to give the title compound as a white solid (400 mg, 10.4%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.95 (s, 1H), 8.46 (m, 1H), 8.20 (m, 1H), 7.75 (d, 1H), 7.53 (m, 1H).
Reaction SMILES: [CH2:1]=O.[F:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]4[CH:20]=[N:21][N:22]([CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH:23]=4)[CH:18]=3)[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1.[Na].N>ClCCl.CO>[F:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]4[CH:20]=[N:21][N:22]([CH:24]5[CH2:25][CH2:26][N:27]([CH3:1])[CH2:28][CH2:29]5)[CH:23]=4)[CH:18]=3)[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(F)cccc2o1
Reactant: C=O
Agent: N
Agent: [Na]
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(n2cc(-c3cnc(N)c(-c4nc5c(F)cccc5o4)c3)cn2)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
37% aqueous formaldehyde (0.015 ml) at 0° C., was added to a stirred solution of 3-(4-fluoro-1,3-benzoxazol-2-yl)-5-[1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine dissolved in dichloromethane (6 ml) and methanol (6 ml) over a period of 5 minutes. The resulting mixture was stirred at 0° C. for 10 minutes. Sodium triacetoxyhydroborate (233 mg) was added at 0° C. to the mixture and stirred at 0° C. for 1 hour. A solution of 7N ammonia in methanol (20 ml) was added to the mixture and adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel eluting with 2 to 6% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness and tritured in hot acetonitrile, filtered and dried under reduce pressure to afford 3-(4-fluoro-1,3-benzoxazol-2-yl)-5-[1-(1-methyl-4-piperidyl)pyrazol-4-yl]pyridin-2-amine (268 mg) as a solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:20])[CH:5]=[C:4]([CH3:27])[N:3]=1.[NH3:28]>C1COCC1.CO>[CH3:27][C:4]1[CH:5]=[C:6]([S:8][CH2:9][C:10]2[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:20])[N:7]=[C:2]([NH2:28])[N:3]=1
Reactant: Cc1cc(SCc2cc3cccc(C)c3nc2-c2ccccc2)nc(Cl)n1
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(SCc2cc3cccc(C)c3nc2-c2ccccc2)nc(N)n1
Temperature: 120 °C
Yield: 20 %

Procedure:
To a solution of Example 85 (100 mg, 0.26 mmol) in THF (1 mL) was added 7N ammonia in methanol (5 mL). The reaction mixture was heated in a microwave at 120° C. for 1 h and concentrated in vacuo. Purification by preparative HPLC (Method 1) gave the title compound as an off-white solid (24 mg, 20%). δH (DMSO-d6) 8.60 (s, 1H), 8.27 (s, 1H), 7.84 (d, J 8.1 Hz, 1H), 7.66-7.70 (m, 2H), 7.60-7.65 (m, 1H), 7.45-7.58 (m, 3H), 6.61 (br s, 2H), 6.28 (s, 1H), 4.54 (s, 2H), 2.69 (s, 3H), 2.08 (s, 3H). LCMS (ES+) 373.2 (M+H)+, RT 2.99 minutes (Method 3).
Reaction SMILES: [C:1]12([CH2:11]O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:13][C:14]1[C:18]([B:19]2[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]2)=[C:17]([CH3:28])[NH:16][N:15]=1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[CH3:13][C:14]1[C:18]([B:19]2[O:23][C:22]([CH3:24])([CH3:25])[C:21]([CH3:27])([CH3:26])[O:20]2)=[C:17]([CH3:28])[N:16]([CH2:11][C:1]23[CH2:10][CH:5]4[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]4)[CH2:8]2)[CH2:2]3)[N:15]=1
Reactant: OCC12CC3CC(CC(C3)C1)C2
Reactant: Cc1n[nH]c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: Cc1nn(CC23CC4CC(CC(C4)C2)C3)c(C)c1B1OC(C)(C)C(C)(C)O1
Reaction time: 8 h

Procedure:
To a solution of 1-adamantanemethanol (0.090 g), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.160 g) and cyanomethylenetributylphosphorane (0.215 g) were added and stirred together in toluene (2 mL) at room temperature. After stirring overnight the reaction was loaded directly onto silica gel and eluted using a gradient of 2% to 20% ethyl acetate/hexanes to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:48][N:49]1[CH2:54][CH2:53][CH2:52][C:51]([NH2:61])([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH2:50]1>CN(C=O)C>[Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:61][C:51]1([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH2:52][CH2:53][CH2:54][N:49]([CH3:48])[CH2:50]1)=[O:6]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Reactant: CN1CCCC(N)(c2ccccc2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCCC(NC(=O)c2cccc(C(F)(F)F)c2Cl)(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 22 h
Yield: 51.9 %

Procedure:
To a solution of 33 mg (0.144 mmol) 2-chloro-3-(trifluoromethyl)benzoic acid (commercial), 75 mg (0.197 mmol) HATU and 90 ul (0.524 mmol) N-ethyldiisopropylamine in DMF (1 ml) was added a solution of 25 mg (0.131 mmol) rac-1-methyl-3-phenyl-piperidin-3-ylamine (Example A.1) in DMF (0.25 ml). The mixture was stirred at room temperature for 22 hours. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate. The solution was washed once with water and twice with a saturated sodium carbonate solution. The aqueous layer was extracted once with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 100%) to provide 27 mg (52%) of the title compound as a light yellow oil. MS (m/e): MS (m/e): 397.2 (M+H)
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([NH:11][CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14](OCC)=[O:15])=[N:3][CH:2]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[O:15]=[C:14]1[N:3]2[CH:2]=[N:1][C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[C:4]2=[N:11][CH:12]=[C:13]1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)C(=CNc1ncnc2ccccc12)C(=O)OCC
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c3ccccc3ncn2c1=O
Temperature: 250 °C
Reaction time: 0.33 h
Yield: 90.8 %

Procedure:
To diethyl [(4-quinazolinylamino)methylene]propanedioate (16.0 g) was added diphenylether (70 ml) which had been heated at 250° C. in advance. The reaction mixture was stirred at 250°-260° C. for 20 minutes and cooled to ambient temperature. To the resultant mixture was added hexane. The mixture was stirred to give crystals, which was washed with hexane and dried. The crude crystals were dissolved in ethyl acetate under heating. After insoluble materials were removed by filtration, the filtrate was concentrated under reduced pressure to a volume of 200 ml. To the concentrate was added hexane and the mixture was allowed to stand at ambient temperature to precipitate crystals, which were separated by filtration, washed with a mixture of ethyl acetate and hexane and dried to give crystalline ethyl 4-oxo-4H-pyrimido[1,2-c]quinazoline-3-carboxylate (12.4 g).
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10](Cl)[C:5]2=[N:4][C:3]=1[CH3:12].Cl.[NH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C>C(O)C(C)C>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([S:22]([NH2:25])(=[O:23])=[O:24])=[CH:20][CH:21]=3)[C:5]2=[N:4][C:3]=1[CH3:12]
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1nc2c(Cl)nccn2c1Br
Agent: Cl
Solvent: CC(C)CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2c(NCc3ccc(S(N)(=O)=O)cc3)nccn2c1Br
Temperature: 108 °C
Reaction time: 16 h
Yield: 29.9 %

Procedure:
To a solution of 3-bromo-8-chloro-2-methyl-imidazo[1,2-a]pyrazine (0.77 g, 3.12 mmol) in iBuOH (10 ml) is added 4-aminomethyl-benzenesulfonamide hydrochloride (1.04 g, 4.69 mmol) and DIPEA (1.63 ml, 9.36 mmol). The reaction is heated to 108° C. and stirred for 16 h. After this time the solution is allowed to cool, resulting in a thick white precipitate. The precipitate is filtered and washed with diethyl ether to give 4-[(3-Bromo-2-methyl-imidazo[1,2-a]pyrazin-8-ylamino)-methyl]-benzenesulphonamide as a white solid (0.37 g, 30%)
Reaction SMILES: [S:1]1[C:5]2[C:6]3[S:11][CH:10]=[CH:9][C:7]=3[S:8][C:4]=2[CH:3]=[CH:2]1.C1C(=O)N([Br:19])C(=O)C1>>[Br:19][C:10]1[S:11][C:6]2[C:5]3[S:1][CH:2]=[CH:3][C:4]=3[S:8][C:7]=2[CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1cc2sc3ccsc3c2s1
Product: Brc1cc2sc3ccsc3c2s1

Procedure:
Compound 2 was synthesized as shown in Scheme 2. Under acid condition, dithieno[3,2-b:2′,3′-d]thiophene (Organic Syntheses, Vol. 83, p. 209 (2006)) was reacted with NBS affording 2-bromodithieno[3,2-b:2′,3′-d]thiophene 7, which underwent Suzuki cross-coupling reaction with boronic acid R1—B(OH)2 (J. Mater. Chem., 2010, 20, 2182-2189) to afford intermediate 8 in 71% yields. Finally 8 was converted to PhN—OFFT-TCN by reacting with n-BuLi and tetracyanoethylene at low temperature in 85% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:6]=[C:5]([NH:15][S:16]([CH2:19][CH2:20][CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:18])=[O:17])[C:4]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34].C[OH:36]>>[OH:36][CH2:23][C:22]([CH3:25])([CH3:24])[CH2:21][CH2:20][CH2:19][S:16]([NH:15][C:5]1[C:4]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])=[C:3]([O:2][CH3:1])[N:8]=[C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:6]=1)(=[O:17])=[O:18]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)CCCC(C)(C)C)nc(-c2ncccn2)nc1OC
Reactant: CO
Product: COc1ccccc1Oc1c(NS(=O)(=O)CCCC(C)(C)CO)nc(-c2ncccn2)nc1OC
Reaction time: 48 h

Procedure:
Streptomyces rimosus subsp. rimosus ATCC10970 maintained on a quarter strength ATCC172 agar slope was inoculated as a loopful of spores into a 300 ml Erlenmeyer flask containing 50 ml of AS-7H inoculum medium. This was allowed to incubate for 2 days at 28° C., 200 rpm on an Infors Multitron Shaker with 1″ throw. 2 mls of this inoculum medium was then transferred to twenty 300 ml Erlenmeyer flask containing 50 ml of AP-5H production medium and incubated under the same conditions for a further 24 hours. At this point 4.5 mg of N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-4,4-dimethyl-1-pentanesulfonamide (Preparation 3) dissolved in 0.5 ml of methanol was added to each of the flasks and the fermentation allowed to continue under the same conditions for a further 20 hours. The flask was then extracted with 200 mls of ethyl acetate and the combined ethyl acetate solubles concentrated to dryness to give a gum solid, 200 mg.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH:28]=[C:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].[CH2:37]([S:39]([NH2:42])(=[O:41])=[O:40])[CH3:38]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:42][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:25][CH:26]=[C:27]([C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[CH2:28][CH2:29]1)=[O:23]
Reactant: Cc1ccc(C)c(Nc2c(C(=O)N3CC=C(c4ccc(F)cc4)CC3)cnc3c(C(=O)O)cnn23)c1
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)N3CC=C(c4ccc(F)cc4)CC3)cnc12
Yield: 40.5 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2,5-dimethylphenylamino)-6-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (45 mg, 0.09 mmol) obtained in step 2 and ethanesulfonamide (49 mg, 0.47 mmol), the title compound (21 mg, 39%) was obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([CH3:13])[CH:7]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[CH3:13][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[CH3:12])[O:5][CH2:4][CH2:3][CH2:2][N:28]1[CH2:29][CH2:30][CH:25]([C:21]2[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=2)[CH2:26][CH2:27]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: Cc1ccc(OCCCCl)cc1C
Product: Cc1ccc(OCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1C

Procedure:
Prepared by Procedure G and Scheme B1 using 4-(3-chloropropoxy)-1,2-dimethylbenzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 409.2 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([CH:15]([CH3:17])[CH3:16])[C:12]([OH:14])=[O:13].[C:18]([CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:23]=1)O)#[N:19]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([CH:15]([CH3:17])[CH3:16])[C:12]([O:14][CH:20]([C:18]#[N:19])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:23]=1)=[O:13]
Reactant: CC(C)C(C(=O)O)c1ccc2ccccc2c1
Reactant: N#CC(O)c1cccc(Oc2ccc(F)cc2)n1
Product: CC(C)C(C(=O)OC(C#N)c1cccc(Oc2ccc(F)cc2)n1)c1ccc2ccccc2c1

Procedure:
Following the procedure of Example 3, 2-(2-naphthyl)-3-methylbutanoic acid is reacted with cyano [6-(4-fluorophenoxy)-2-pyridyl]methanol to give cyano[6-(4-fluorophenoxy)-2-pyridyl]methyl 2-(2-naphthyl)-3-methylbutanoate.
Reaction SMILES: C(O)(=O)C.[Si:5]([O:12][CH2:13][CH:14]=O)([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:30]([O:37][C:38]1[CH:62]=[CH:61][C:60]([CH:63]2[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]2)=[CH:59][C:39]=1[C:40]([NH:42][C:43]1[CH:52]=[C:51]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH:50]=[CH:49][C:44]=1[C:45]([O:47][CH3:48])=[O:46])=[O:41])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1>[CH2:30]([O:37][C:38]1[CH:62]=[CH:61][C:60]([CH:63]2[CH2:64][CH2:65][N:66]([CH2:14][CH2:13][O:12][Si:5]([C:8]([CH3:9])([CH3:10])[CH3:11])([CH3:6])[CH3:7])[CH2:67][CH2:68]2)=[CH:59][C:39]=1[C:40]([NH:42][C:43]1[CH:52]=[C:51]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH:50]=[CH:49][C:44]=1[C:45]([O:47][CH3:48])=[O:46])=[O:41])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCNCC2)ccc1OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCN(CCO[Si](C)(C)C(C)(C)C)CC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
Acetic acid (0.023 mL), 2-(tert-butyldimethylsilyloxy)acetaldehyde (0.046 mL), and sodium triacetoxyborohydride (0.11 g) were sequentially added to a tetrahydrofuran (1.0 mL) solution of methyl 2-(2-(benzyloxy)-5-(piperidin-4-yl)benzamido)-4-phenylbenzoate (0.11 g), followed by stirring at room temperature for 13 hours. The solvent was evaporated under reduced pressure, and ethyl acetate was added to the residue. After removal of the insoluble substance by filtration, a saturated aqueous solution of sodium bicarbonate was added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-92% chloroform/methanol] to obtain 0.13 g of methyl 2-(2-(benzyloxy)-5-(1-(2-(tert-butyldimethylsilyloxy)ethyl)piperidin-4-yl)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: I[C:2]1[NH:6][C:5]([CH3:7])=[N:4][CH:3]=1.C(N(CC)CC)C.[Cl:15][C:16]1[CH:17]=[C:18]([C:22]#[CH:23])[CH:19]=[CH:20][CH:21]=1>CN(C=O)C.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>[Cl:15][C:16]1[CH:17]=[C:18]([C:22]#[C:23][C:2]2[N:6]=[C:5]([CH3:7])[NH:4][CH:3]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: C#Cc1cccc(Cl)c1
Reactant: Cc1ncc(I)[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.7 %

Procedure:
To a solution of 500 mg (2.40 mmol) of 5-iodo-2-methyl-1H-imidazole (CAS: [73746-45-9]) in 7 ml of DMF were added under an argon atmosphere 118 mg (0.17 mmol) of Bis(triphenylphosphine)palladium dichloride and 0.67 ml (4.81 mmol) of triethylamine. The mixture was stirred for 10 min at room temperature. Then 0.52 ml (575 mg, 4.09 mmol) of 3-chloro-1-ethynyl-benzene and 13.7 mg (0.072 mmol) of copper(I) iodide were added and the mixture was stirred for 1.5 h at 60° C. The mixture was concentrated in vaccuo, dissolved in a minimal volume of methylene chloride and purified by chromatography on 20 g of silicagel (gradient Heptane/EtOAc 85:15->EtOAc) to yield 430 mg (83%) of the title compound as an orange crystalline solid, MS: m/e=217.2, 219.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:18][C:17]3[CH:19]=[C:20](B4OC(C)(C)C(C)(C)O4)[CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:33]1[CH:41]=[CH:40][C:36]([C:37]([NH2:39])=[O:38])=[CH:35][N:34]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]2[CH2:18][C:17]3[CH:19]=[C:20]([C:33]4[CH:41]=[CH:40][C:36]([C:37](=[O:38])[NH2:39])=[CH:35][N:34]=4)[CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: NC(=O)c1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(B4OC(C)(C)C(C)(C)O4)ccc3O2)CC1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(C(N)=O)cn4)ccc3O2)CC1

Procedure:
The title compound is prepared from 4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carboxylic acid tert-butyl ester and 6-bromonicotinamide following a procedure analogous to that described in Example 1. LC (method 6): tR=1.20 min; Mass spectrum (ESI+): m/z=424 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[O:9][C:10]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:11][C:12](=[O:14])[CH:13]=1.[C:21]([O:25][C:26]([N:28]1[C:41]2[CH:40]=[CH:39][CH:38]=[C:37](B3OC(C)(C)C(C)(C)O3)[C:36]=2[S:35][C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:27])([CH3:24])([CH3:23])[CH3:22]>O1CCOCC1>[C:21]([O:25][C:26]([N:28]1[C:29]2[CH:30]=[CH:31][CH:32]=[C:33]([C:8]3[O:9][C:10]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:11][C:12](=[O:14])[CH:13]=3)[C:34]=2[S:35][C:36]2[C:41]1=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=c1cc(Cl)oc(N2CCOCC2)c1
Reactant: CC(C)(C)OC(=O)N1c2ccccc2Sc2c(B3OC(C)(C)C(C)(C)O3)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1c2ccccc2Sc2c(-c3cc(=O)cc(N4CCOCC4)o3)cccc21
Temperature: 100 °C
Yield: 100.1 %

Procedure:
Powdered potassium carbonate (2.03 g, 14.68 mmol) and 2-chloro-6-morpholin-4-yl-pyran-4-one (3) (1.44 g, 6.70 mmol) were added to a stirred solution of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenothiazine-10-carboxylic acid tert-butyl ester (2.85 g, 6.70 mmol) in anhydrous dioxane (20 ml) and the mixture degassed (sonication for 20 minutes then saturated with N2) thoroughly. Tetrakis (triphenylphosphine) palladium was then added in a single portion and the mixture degassed (sonication for 20 minutes then saturated with N2) once again before a reflux condenser was attached and the mixture heated to 100° C. under a nitrogen atmosphere for 20 hours. Water (30 ml) was added and the mixture extracted with EtOAc (3×30 ml). The organic extracts were then dried using MgSO4, filtered and concentrated in vacuo to yield a dark brown, crystalline solid (3.21 g, 100%) that was taken forward with no further purification. m/z (LC-MS, ESP): 479 [M+H]+, RT=4.55 mins.