Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C@H:9]1[C@H:14]([O:15]CC2C=CC=CC=2)[C@@H:13]([O:23]CC2C=CC=CC=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH3:38])=[C:33]([CH2:39][C:40]3[CH:49]=[CH:48][C:43]4[O:44][CH2:45][CH2:46][O:47][C:42]=4[CH:41]=3)[CH:32]=2)[O:11][C@@H:10]1[CH2:50][O:51][C:52](=[O:65])[C@H:53]([NH:57][C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH:54]([CH3:56])[CH3:55])C1C=CC=CC=1>C(OCC)(=O)C.CO.[OH-].[Pd+2].[OH-]>[O:44]1[C:43]2[CH:48]=[CH:49][C:40]([CH2:39][C:33]3[CH:32]=[C:31]([C@@H:12]4[O:11][C@H:10]([CH2:50][O:51][C:52](=[O:65])[C@H:53]([NH:57][C:58]([O:60][C:61]([CH3:63])([CH3:62])[CH3:64])=[O:59])[CH:54]([CH3:56])[CH3:55])[C@@H:9]([OH:8])[C@H:14]([OH:15])[C@H:13]4[OH:23])[CH:36]=[CH:35][C:34]=3[CH2:37][CH3:38])=[CH:41][C:42]=2[O:47][CH2:46][CH2:45]1
Reactant: CCc1ccc([C@@H]2O[C@H](COC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc2c(c1)OCCO2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1ccc([C@@H]2O[C@H](COC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.3 %

Procedure:
To a stirred solution of (R)-2-tert-butoxycarbonylamino-3-methyl-butyric acid (2R,3R,4R,5S,65)-3,4,5-tris-benzyloxy-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-tetrahydro-pyran-2-ylmethyl ester (4.5 g, 5.0 mmol) in ethyl acetate: methanol (1:4 mixture, 50 ml) was added palladium hydroxide (2.0 g). After stirring for overnight at room temperature, reaction mixture was filtered through celite bed, concentrated and purified by silica gel column chromatography to give 3.12 g of (R)-2-tert-butoxycarbonylamino-3-methyl-butyric acid (2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester as a white solid.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[C:23]4[CH:24]=[CH:25][C:26]([C:28]5[NH:29][C:30]([C:33]#[N:34])=[CH:31][CH:32]=5)=[CH:27][C:22]=4[C:21]([CH3:36])([CH3:35])[O:20][CH:19]3[CH3:37])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:38](=O)([O-])[O-].[K+].[K+].IC.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[C:33]([C:30]1[N:29]([CH3:38])[C:28]([C:26]2[CH:25]=[CH:24][C:23]3[N:18]([C:16]([O:15][CH2:14][CH:12]4[C:13]5[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=5[C:6]5[C:11]4=[CH:10][CH:9]=[CH:8][CH:7]=5)=[O:17])[CH:19]([CH3:37])[O:20][C:21]([CH3:36])([CH3:35])[C:22]=3[CH:27]=2)=[CH:32][CH:31]=1)#[N:34]
Reactant: CC1OC(C)(C)c2cc(-c3ccc(C#N)[nH]3)ccc2N1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CC1OC(C)(C)c2cc(-c3ccc(C#N)n3C)ccc2N1C(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
A mixture of 9H-fluoren-9-ylmethyl-6-[5-cyano-1H-pyrrol-2-yl]-2,4,4-trimethyl-2H-3,1-benzoxazine-1(4H)-carboxylate (0.4 g, 0.8 mmol) and potassium carbonate (1.5 g) in anhydrous DMF was treated at ambient temperature under a blanket of nitrogen with iodomethane (1.5 mL, excess). The mixture was stirred for 30 minutes. A saturated ammonium sulfate solution (50 mL) and ethyl acetate (50 mL) was added. The organic layer was separated and aqueous layer was extracted with ethyl acetate (3×15 mL). The combined organic layers were dried (MgSO4), evaporated to yield the title compound as a white solid (0.35 g, 87%): mp 63-64° C.; 1H-NMR (DMSO-d6) δ 7.90 (m, 2H), 7.62 (d, 1H, J=7.7 Hz), 7.58 (d, 1H, J=7.7 Hz), 7.40 (m, 2H), 7.29-7.32 (m, 3H), 7.14 (dd, 1H, J=8.1, 1.9 Hz), 7.01-7.04 (m, 2H), 6.33 (d, 1H,J=4.3 Hz), 5.31 (q, 1H, J=5.8 Hz), 4.88 (dd, 1H, J=10.8, 5.0 Hz), 4.65 (dd, 1H, J=10.8, 4.6 Hz), 4.34 (t, 1H, J=4.6 Hz), 3.71 (s, 3H), 1.52 (s, 3H), 1.21 (s, 3H), 1.06 (d, 3H, J=5.4 Hz); MS (ESI) m/z 504 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:12]3[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]3)[CH2:7][C@@H:6]3[CH2:19][O:20][CH2:21][CH2:22][N:5]3[C:4]=2[N:3]=1.[NH:23]1[C:31]2[C:26](=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24]1>O1CCOCC1.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH:23]1[C:31]2[C:26](=[C:27]([C:2]3[N:11]=[CH:10][C:9]4[N:8]([CH:12]5[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]5)[CH2:7][C@@H:6]5[CH2:19][O:20][CH2:21][CH2:22][N:5]5[C:4]=4[N:3]=3)[CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24]1
Reactant: OC1CCC(N2C[C@@H]3COCCN3c3nc(Cl)ncc32)CC1
Reactant: OB(O)c1cccc2[nH]ccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: OC1CCC(N2C[C@@H]3COCCN3c3nc(-c4cccc5[nH]ccc45)ncc32)CC1

Procedure:
The title compound was prepared in a manner similar to Example 2 using (R)-4-(2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)cyclohexanol (PREPARATION x63, 30 mg, 0.092 mmol), 1H-indol-4-ylboronic acid (71.9 mg, 0.447 mmol) and PdCl2(dppf) (8.17 mg, 0.011 mmol) in dioxane (2 mL) and aqueous saturated NaHCO3 (0.4 mL) (2 mg, 5%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32-1.85 (m, 6H), 2.78-2.93 (m, 1H), 2.96-3.11 (m, 1H), 3.50-3.75 (m, 6H), 3.81-3.90 (m, 2H), 3.94-4.10 (m, 1H), 4.36-4.45 (m, 1H), 4.49-4.60 (m, 1H), 6.51-6.62 (m, 1H), 7.02-7.19 (m, 1H), 7.27-7.45 (m, 3H), 7.80-7.98 (m, 2H), 11.04-11.16 (m, 1H); ESI-MS m/z [M+H]+ calc'd for C23H27N5O2, 406.22. found 406.4.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[C:26]([F:27])=[CH:25][C:24]([F:28])=[CH:23][C:22]=2[F:29])=[N:10]1.C1C(=O)N([Br:37])C(=O)C1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][Br:37])[NH:12][C:11]([C:21]2[C:22]([F:29])=[CH:23][C:24]([F:28])=[CH:25][C:26]=2[F:27])=[N:10]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=C(C)NC(c2c(F)cc(F)cc2F)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CBr)NC(c2c(F)cc(F)cc2F)=NC1c1ccc(F)cc1Br
Yield: 55.6 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(2,4,6-trifluorophenyl)-1,4-dihydropyrimidine-5-carboxylate (6.31 g, 13.4 mmol) (The compound was synthesized according to the procedure as described in CN200610098646.3) was reacted with NBS (2.87 g, 16.1 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (4.1 g, 55%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C([NH:5][C:6]([NH:8][C@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[CH2:10]O)=[S:7])(C)(C)C.[ClH:19]>CC(O)C>[ClH:19].[ClH:19].[N:16]1[CH:17]=[CH:18][C:13]([CH2:12][C@@H:9]2[CH2:10][S:7][C:6]([NH2:5])=[N:8]2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)NC(=S)N[C@@H](CO)Cc1ccncc1
Agent: Cl
Solvent: CC(C)O
Product: NC1=N[C@H](Cc2ccncc2)CS1

Procedure:
The process is performed under the conditions of Example 1 starting with 0.46 g of N-(tert-butyl)-N′-[(1R)-2-hydroxy-1-(4-pyridylmethyl)ethyl]thiourea which is heated in 5 cm3 of aqueous 5 N hydrochloric acid for 16 hours at a temperature in the region of 100° C. After concentration of the reaction mass under reduced pressure (5 kPa) at a temperature in the region of 40° C., an oil is obtained which is taken up in 3 cm3 of 2-propanol. The resulting crystalline precipitate is spin-filtered, washed with 2-propanol and air-dried. 0.1 g of (+)-(4R)-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine dihydrochloride is obtained in the form of an orange-colored solid melting at 150° C. (αD20=+38.3±0.9 at a concentration of 0.5% in MeOH).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:34]([CH3:36])[CH3:35])[C:9]1[S:10][C:11]([C:14]2[CH:15]=[C:16]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:17]3[N:18]([CH:20]=[C:21]([C:23](OCC)=[O:24])[N:22]=3)[CH:19]=2)=[CH:12][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[OH:24][CH2:23][C:21]1[N:22]=[C:17]2[C:16]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:15][C:14]([C:11]3[S:10][C:9]([N:8]([CH:34]([CH3:35])[CH3:36])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[N:13][CH:12]=3)=[CH:19][N:18]2[CH:20]=1
Reactant: CCOC(=O)c1cn2cc(-c3cnc(N(C(=O)OC(C)(C)C)C(C)C)s3)cc(-c3ccccc3)c2n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)N(C(=O)OC(C)(C)C)c1ncc(-c2cc(-c3ccccc3)c3nc(CO)cn3c2)s1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of ethyl 6-(2-(tert-butoxycarbonyl-(isopropyl)amino)thiazol-5-yl)-8-phenylimidazo[1,2-a]pyridine-2-carboxylate (100 mg, 0.2 mmol) in ether was cooled in an ice bath and treated with solid LAH (15 mg, 0.4 mmol). The mixture was stirred at 0° C. for 2 hours. The reaction was quenched with water, diluted with ethyl acetate and washed with water, brine and concentrated to give tert-butyl 5-(2-(hydroxymethyl)-8-phenylimidazo[1,2-a]pyridin-6-yl)thiazol-2-yl(isopropyl)carbamate. LCMS (Conditions C): 3.36 min (RT); (M+H)+=465.32 (100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:4]=1[CH:5]=O.[CH2:15]([N:19]1[C:23](=[O:24])[CH2:22][NH:21][C:20]1=[O:25])[CH2:16][CH2:17][CH3:18].C(CN)O>O.C(O)C>[CH2:15]([N:19]1[C:23](=[O:24])[C:22](=[CH:5][C:4]2[CH:7]=[C:8]([O:13][CH3:14])[C:9]([O:11][CH3:12])=[CH:10][C:3]=2[O:2][CH3:1])[NH:21][C:20]1=[O:25])[CH2:16][CH2:17][CH3:18]
Reactant: COc1cc(OC)c(OC)cc1C=O
Reactant: CCCCN1C(=O)CNC1=O
Solvent: CCO
Solvent: NCCO
Solvent: O
Product: CCCCN1C(=O)NC(=Cc2cc(OC)c(OC)cc2OC)C1=O
Yield: 86.7 %

Procedure:
A mixture of 2,4,5-trimethoxybenzaldehyde (9.8 g; 0.05 mole), 3-n-butylhydantoin (7.8 g; 0.05 mole) and ethanolamine (4.6 g; 0.075 mole) in water/ethanol (50 ml/30 ml) was stirred and boiled under reflux for 3 hours. The cloudy solution was cooled in the refrigerator and the resultant yellow solid filtered off, washed with water, sucked dry and recrystallised from ethanol to give the title compound (14.5 g; 87%) m.p. 170° C.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:6][CH:5]=[CH:4][C:3]=1I.C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[C:66](=[NH:79])([C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:66](=[N:79][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:8][C:9]([F:12])([F:11])[F:10])[C:2]=1[F:1])([C:73]1[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=1)[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Fc1c(I)cccc1OC(F)(F)F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Fc1c(N=C(c2ccccc2)c2ccccc2)cccc1OC(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of 2-fluoro-1-iodo-3-(trifluoromethoxy)benzene (25 g, 81 mmol) in dry toluene (200 mL) was added Cs2CO3 (38.7 g, 120 mmol), Pd2(dba)3 (7.42 g, 8.1 mmol), BINAP (10.8 g, 16.2 mmol) and benzhydrylideneamine (19.6 g, 108 mmol). The reaction mixture was refluxed for 8 h with stirring and then cooled to RT. The organic layer was washed with water and brine and then dried over MgSO4. After removal of solvent in vacuo, the residue was purified by column chromatography on silica gel (solvent gradient from 100% n-hexane to n-hexane/EtOAc 20:1) to afford the title compound as a pale yellow oil. 1H NMR (CDCl3, 400 MHz): δ 7.72 (s, 1H, ArH,), 7.70 (s, 1H, ArH), 7.45-7.42 (m, 1H, ArH,), 7.37-7.33 (m, 2H, ArH), 7.25-7.17 (m, 3H, ArH), 7.06 (s, 1H, ArH), 7.05 (s, 1H, ArH,), 6.84 (t, 1H, J=8 Hz, ArH), 6.78 (t, 1H, J=8 Hz, ArH), 6.67-6.64 (m, 1H, ArH).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([OH:18])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].[N+:21]([C:24]1[CH:29]=[C:28]([S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])[CH:27]=[CH:26][C:25]=1Cl)([O-:23])=[O:22]>C1COCC1>[CH2:16]([O:15][C:13](=[O:14])[C:11]1[CH:12]=[C:2]([O:1][C:25]2[CH:26]=[CH:27][C:28]([S:30]([C:33]([F:35])([F:36])[F:34])(=[O:32])=[O:31])=[CH:29][C:24]=2[N+:21]([O-:23])=[O:22])[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:9][C:10]=1[OH:18])[CH3:17]
Reactant: CCOC(=O)c1cc(O)c(C(=O)OCC)cc1O
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[N+](=O)[O-])c(C(=O)OCC)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of diethyl 2,5-dihydroxyterephthalate (100 mg, 0.393 mmol) in THF was added sodium hydride (32 mg of 60% dispersion in mineral oil) followed by 2-nitro-4-(trifluoromethylsulfonyl)chlorobenzene (228 mg, 0.787 mmol). The mixture was stirred at room temperature for overnight. The reaction was extracted with ethyl acetate, the organic layer was washed with water and brine, dried, concentrated and purified to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 10.77 (br s, 1H, OH), 8.78 (d, J=2.3 Hz, 1H), 8.22 (dd, J=2.3 & 9.0 Hz, 1H), 7.82(s, 1H), 7.56 (s, 1H), 7.19 (d, J=9.0 Hz, 1H), 4.32 (q, J=7.2 Hz, 2H, OCH2CH3), 4.09 (q, J=7.2 Hz, 2H, OCH2CH3), 1.3 (t, J=7.2 Hz, 3H, OCH2CH3), 0.92 (t, J=7.2 Hz, 3H, OCH2CH3).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10])#[N:2].C([Sn]([N:24]=[N+:25]=[N-:26])(CCCC)CCCC)CCC>C1(C)C(C)=CC=CC=1.C(OCC)C>[CH3:10][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]1[N:24]=[N:25][NH:26][N:2]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: COc1ccccc1C#N
Solvent: CCOCC
Solvent: Cc1ccccc1C
Product: COc1ccccc1-c1nn[nH]n1
Yield: 98.1 %

Procedure:
A mixture of 1-cyano-2-methoxybenzene (1.02 g, 7.7 mmol) and tributyltin azide (3.4 g, 10.0 mmol) in 3.0 mL of xylene was heated under reflux for 5 hours. The reaction mixture then was cooled and diluted with diethyl ether. Anhydrous hydrochloric acid was bubbled into the mixture and a white precipitate formed. The precipitate was collected by suction filtration and washed repeatedly with diethyl ether. Drying gave 5-(2-methoxyphenyl)-2H-tetrazole (1.33 g, 7.55 mmol).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH:10]1(B(O)O)[CH2:12][CH2:11]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[C:8]([C:5]1[CH:4]=[CH:3][C:2]([CH:10]2[CH2:12][CH2:11]2)=[CH:7][N:6]=1)#[N:9]
Reactant: OB(O)C1CC1
Reactant: N#Cc1ccc(Cl)cn1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1ccc(C2CC2)cn1
Temperature: 100 °C

Procedure:
To a mixture of 5-chloro-2-cyanopyridine (1.25 g, 9.02 mmol), cyclopropylboronic acid (1.00 g, 11.7 mmol), potassium phosphate (6.70 g, 31.6 mmol), tricyclohexylphosphine (380 mg, 1.4 mmol), toluene (200 mL), and water (2 mL) under argon was added palladium acetate (150 mg, 0.68 mmol). The mixture was heated at 100° C. overnight and then cooled to rt. The mixture was filtered through Celite and the filter cake was washed with EtOAc. The filtrate was washed with water, dried (Na2SO4), and concentrated. The residue was purified by silica gel column (EtOAc/hexane: 0-50%) to yield a light yellow oil which becomes solid while standing at room temperature.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH2:11][O:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[CH:17][C:18]3[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>>[Cl:1][C:2]1[C:12]2[CH2:11][O:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[CH:17][C:18]3[CH:19]=[C:20]([NH:24][S:26]([CH3:25])(=[O:28])=[O:27])[CH:21]=[CH:22][CH:23]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(C=C2c3ccccc3OCc3c(Cl)cccc32)c1
Product: CS(=O)(=O)Nc1cccc(C=C2c3ccccc3OCc3c(Cl)cccc32)c1

Procedure:
Following procedures essentially as described in Example 90, the title compound is prepared from 3-(7-chloro-6H-dibenzo[b,e]oxepin-11-ylidenemethyl)-phenylamine and methanesulfonyl chloride. Elute on silica gel with 15% ethyl acetate:toluene gave 530 mg product (86%). 1H NMR (400 MHz, CDCl3) δ 7.463-7.443 (d, 1H), 7.358-7.337 (d, 1H), 7.230-7.155 (m, 2H), 7.116-7.077 (t, 1H), 7.016-6.840 (m, 7H), 6.264 (s, 1H), 5.563 (s, 2H), 2.88 (s, 3H) MS m/z: 410.1 (M−−1).
Reaction SMILES: [CH2:1]([NH:7][C:8](=[NH:25])[NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15]2[O:16][C:17]([C:20](=O)[N:21]([CH3:23])[CH3:22])=[CH:18][CH:19]=2)[N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].B#B.Cl>O1CCCC1>[CH2:1]([NH:7][C:8](=[NH:25])[NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15]2[O:16][C:17]([CH2:20][N:21]([CH3:22])[CH3:23])=[CH:18][CH:19]=2)[N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCNC(=N)Nc1nc(-c2ccc(C(=O)N(C)C)o2)cs1
Agent: B#B
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCNC(=N)Nc1nc(-c2ccc(CN(C)C)o2)cs1

Procedure:
2-(3-n-Hexylguanidino)-4-(5-[N,N-dimethylcarbamoyl]-2-furyl)thiazole (1.77 g., 4 mmole) was reduced with an excess of diborane in tetrahydrofuran, substantially according to the procedure of Example 1. At the end of the reduction, 20 ml. of 6N hydrochloric acid was added dropwise, very slowly, and then the mixture was heated at ca 90° C. to removed the majority of the tetrahydrofuran. The aqueous residue was made alkaline with 10N sodium hydroxide solution and then it was extracted with n-butanol. The dried (Na2SO4) extracts were evaporated in vacuo to give a dark-colored oil which was purified by chromatography on silica gel using 1:10 methanol-chloroform. This afforded the title compound, 950 mg, as an oil.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[F:19][C:20]1[C:21]([C:49]2[CH:54]=[CH:53][C:52]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=3[OH:61])=[CH:51][CH:50]=2)=[CH:22][C:23]2[N:27]=[C:26]([O:28][C:29]3[CH:30]=[CH:31][C:32]([CH3:39])=[C:33]([CH:38]=3)[C:34]([O:36]C)=[O:35])[N:25](COCC[Si](C)(C)C)[C:24]=2[CH:48]=1>C1COCC1>[F:19][C:20]1[C:21]([C:49]2[CH:54]=[CH:53][C:52]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=3[OH:61])=[CH:51][CH:50]=2)=[CH:22][C:23]2[N:27]=[C:26]([O:28][C:29]3[CH:30]=[CH:31][C:32]([CH3:39])=[C:33]([CH:38]=3)[C:34]([OH:36])=[O:35])[NH:25][C:24]=2[CH:48]=1
Reactant: COC(=O)c1cc(Oc2nc3cc(-c4ccc(-c5ccccc5O)cc4)c(F)cc3n2COCC[Si](C)(C)C)ccc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(Oc2nc3cc(-c4ccc(-c5ccccc5O)cc4)c(F)cc3[nH]2)cc1C(=O)O
Temperature: 80 °C

Procedure:
TBAF (1 M in THF) (0.63 mL, 0.63 mmol) was added to a solution of methyl 5-[(6-fluoro-5-(2′-hydroxybiphenyl-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]-2-methylbenzoate (75 mg, 0.125 mmol) in THF (10 mL). The reaction was heated at 80° C. for 6 h. Volatiles were removed and the residue was purified by HPLC eluting with 20-80% MeCN:water. The resulting white solid was dissolved in MeOH (3 mL) and water (2 mL). Aqueous 5 M NaOH (250 μl) was added. The solution was heated at 70° C. for 30 min. Volatiles were removed and the residue was re-dissolved in 10 mL water and extracted with ethyl acetate to afford the title compound as a white solid product. LC/MS: calculated for C27H19FN2O4 454.45, observed m/e 455(M+H)+ (1.97/4 min). 1H-NMR (500 MHz, D6-acetone): 8.02-6.98 (13H, m), 2.62 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:50]=[CH:49][CH:48]=[CH:47][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34](B3OC(C)(C)C(C)(C)O3)[CH:33]=2)=[CH:13][CH:12]=1.Br[C:52]1[N:53]([CH2:57][CH2:58][CH2:59][O:60][CH3:61])[CH:54]=[CH:55][N:56]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.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>[CH3:1][O:2][C:3]1[CH:50]=[CH:49][CH:48]=[CH:47][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:52]3[N:53]([CH2:57][CH2:58][CH2:59][O:60][CH3:61])[CH:54]=[CH:55][N:56]=3)[CH:33]=2)=[CH:15][CH:16]=1
Reactant: COCCCn1ccnc1Br
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cccc(B3OC(C)(C)C(C)(C)O3)c2)cc1
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: CCO
Solvent: COCCOC
Product: COCCCn1ccnc1-c1cccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)c1

Procedure:
The mixture of 0.050 g of tetrakis(triphenylphosphine)palladium(0) in 1.0 ml of 1,2-dimethoxyethane is admixed with the solution of 0.319 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzyloxy]piperidine-1-carboxylate and 0.144 g of 2-bromo-1-(3-methoxypropyl)-1H-imidazole in 2.0 ml of 1,2-dimethoxyethane and 0.3 ml of ethanol. The reaction mixture is admixed with 0.9 ml of 2M sodium carbonate solution and stirred at reflux over 20 hours. The resulting reaction solution is concentrated by evaporation, admixed with 1:1 water/brine mixture (30 ml) and extracted with ethyl acetate (2×30 ml). The organic phases are washed with brine (30 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.15 (97:3 dichloromethane-methanol); Rt=5.23.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=O)[CH:2]=1.[OH-].[K+].O.NN>C(O)CO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:2]=1
Reactant: O=C(c1cccnc1)c1cccnc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: c1cncc(Cc2cccnc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dipyridin-3-ylmethanone (1-1, 2.630 g, 14.28 mmol) was suspended in ethylene glycol (28 mL). KOH (1.682 g, 29.98 mmol) was added and the reaction was stirred at RT for 1 hr until most of the solids were dissolved. Hydrazine monohydrate (1.596 mL, 32.84 mmol) was added and the mixture was heated to 185° C. After 1 hr 45 min, the reaction was cooled to RT, diluted with H2O (150 mL), and extracted with CH2Cl2 (4×100 mL). The combined organics were washed with water, washed with brine (2×), dried over Na2SO4, filtered, and concentrated in vacuo to afford 3-(pyridin-3-ylmethyl)pyridine as a light yellow solid. 1H NMR (CDCl3) δ 8.52-8.49 (m, 4H), 7.47-7.45 (m, 2H), 7.25-7.22 (m, 2H), 3.99 (s, 2H). [M+H]+=171.2.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[CH2:14]([NH2:17])[CH2:15][NH2:16].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][N:16]([CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH2:15][CH2:14][N:17]([CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: NCCN
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc2nc(CN(CCN(Cc3ccc4ccccc4n3)Cc3ccc4ccccc4n3)Cc3ccc4ccccc4n3)ccc2c1
Yield: 89.6 %

Procedure:
A mixture of 2-chloromethylquinoline hydrochloride (1.07 g, 5 mmol), ethylenediamine (75.0 mg 1.25 mmol), potassium carbonate (2.07 g, 15 mmol) and acetonitrile (10 mL) was refluxed by heating for 48 hours. The solvent was evaporated under reduced pressure, and then the residue was separated by phase separation using chloroform and water. The organic layer was dried, and the solvent was evaporated. The residue was washed with acetone to obtain the objective compound as white powder (0.70 g, 89%).