Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][C@@H:12]([N:16]3[C:20]4=[C:21]5[CH:27]=[CH:26][NH:25][C:22]5=[N:23][CH:24]=[C:19]4[NH:18][C:17]3=[O:28])[CH2:11]2)=[N:8][CH:9]=1)([O-])=O.O.C([O-])=O.[NH4+]>C(O)C.O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][C@@H:12]([N:16]3[C:20]4=[C:21]5[CH:27]=[CH:26][NH:25][C:22]5=[N:23][CH:24]=[C:19]4[NH:18][C:17]3=[O:28])[CH2:11]2)=[N:8][CH:9]=1
Reactant: O=c1[nH]c2cnc3[nH]ccc3c2n1[C@@H]1CCCN(c2ccc([N+](=O)[O-])cn2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(N2CCC[C@@H](n3c(=O)[nH]c4cnc5[nH]ccc5c43)C2)nc1
Temperature: 75 °C
Reaction time: 0.83 h
Yield: 47.8 %

Procedure:
To a solution of 1-[(3R)-1-(5-nitro-2-pyridinyl)-3-piperidinyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (19.3 mg) in ethanol (3 mL), tetrahydrofuran (1 mL), and water (0.15 mL) was added 10% Pd—C (50% wet, 10 mg) and ammonium formate (32 mg). After stirring for 50 minutes at 75° C., catalyst was removed by filtration, and solvent was also removed under reduced pressure. The residue was dissolved in EtOAc, washed with saturated aqueous sodium hydrogencarbonate, and brine, dried over MgSO4, evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:methanol=10:1 to 8:1) to give 1-[(3R)-1-(5-amino-2-pyridinyl)-3-piperidinyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (8.5 mg) as a pale brown crystals.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[F:14][C:15]1[CH:31]=[CH:30][C:18]([O:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][NH2:29])=[CH:22][CH:21]=2)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[F:14][C:15]1[CH:31]=[CH:30][C:18]([O:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][N:29]3[CH2:11][C:5]4[C:4](=[C:9]([I:10])[CH:8]=[CH:7][CH:6]=4)[C:3]3=[O:13])=[CH:22][CH:21]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1c(I)cccc1CBr
Reactant: NCCCc1ccc(Oc2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1c2c(I)cccc2CN1CCCc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 25.2 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (0.245 g, 0.7 mmol), 3-[4-(4-fluoro-phenoxy)phenyl]-propylamine (0.193 g, 0.8 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-{3-[4-(4-fluoro-phenoxy)-phenyl]-propyl}-7-iodo-2,3-dihydro-isoindol-1-one (0.086 g, 25%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.01 (m, 2H), 2.65 (t, 2H), 3.67 (t, 2H), 4.26 (s, 2H), 6.84-7.42 (m, 10H), 7.90 (d, 1H). GC-MS: m/z 487 (M)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.[OH-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].Cl>O1CCOCC1>[CH2:16]([O:15][C:13]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)C1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Yield: 100 %

Procedure:
A solution of piperidine-4-carboxylic acid (4.7 g, 36 mmol) in 0.5M aqueous sodium hydroxide (160 ml, 80 mmol) and dioxan (50 ml) was treated with benzyl chloroformate (4.3 ml, 5.13 g, 30 mmol). After 1 hour the mixture was acidified with 5M aqueous hydrochloric acid and extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, then dried and evaporated affording an oil (7.9 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[CH:26][C:27]([Br:30])=[C:28]([Br:29])[C:4]=2[N:3]=1>N.CO>[Cl:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]2[OH:9])[C:5]2[CH:25]=[CH:26][C:27]([Br:30])=[C:28]([Br:29])[C:4]=2[N:3]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3c(Br)c(Br)ccc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Solvent: CO
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3c(Br)c(Br)ccc32)[C@H](O)[C@@H]1O

Procedure:
A solution of 0.529 g (0.930 mmol) of 84 in 25 mL of NH3 /MeOH was stirred in a pressure bottle at room temperature for 5 hr. Volatile materials were removed by evaporation and coevaporation with MeOH (3×, bath temperature<40° C.). The resulting solid was recrystallized from MeOH/H2O to give 0.316 g (2 crops, 77%) of 85 as white crystals. MP: 167°-169° C. MS: (Cl) m/e 440.8837 (20%, MH+ =440.8852). 1H NMR (DMSO-d6): δ8.05 (d, 1,7-H, J7-6 =8.5 Hz), 7.59 (d, 1,6-H), 5.89 (d, 1,1'-H, J1'-2' =7.5 Hz), 5.51 (d, 1,2'-OH, J2'-2'OH =6.5 Hz), 5.28 (d, 1,3'-OH, J3'-3'OH =4.5 Hz), 5.27 (t, 1,5'-OH, J5'-5'OH =5.0 Hz), 4.40 (m, 1,2'-H, J2'-3' =5.5 Hz), 4.13 (m, 1,3'H, J3'-4' =2.0 Hz), 4.00 (m, 1, 4'-H, J4'-5" =3.5 Hz), 3.68 (m, 2,5'-H and 5"-H, J5'-5" =12.0 Hz). 13H NMR (DMSO-d6): δ141.70 (C2), 141.58 (C3 a), 132.21 (C7a), 127.42 (C6), 118.06 (C5), 114.08 (C4), 113.87 (C7), 89.45 (C1'), 86.34 (C4'), 71.74 (C2'), 69.62 (C3'), 61.07 (C5'). Anal. Calcd. for C12H11Br2ClN2O4 : C, 32.57; H, 2.51; N, 6.33. Found: C, 32.70; H, 2.33; N, 6.33.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@@H:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[N:19]=3)[N:14]=[CH:13][CH:12]=2)[OH:10])[CH2:4][CH2:3]1.[N:23]1[C:32]2[NH:31][CH2:30][CH2:29][CH2:28][C:27]=2[CH:26]=[CH:25][C:24]=1[CH:33]=O.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH4-].[Na+]>C(Cl)Cl.C(O)C>[CH3:22][O:21][C:18]1[N:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[C:11]2[C@@H:9]([OH:10])[CH2:8][N:5]1[CH2:6][CH2:7][CH:2]([NH:1][CH2:33][C:24]2[CH:25]=[CH:26][C:27]3[CH2:28][CH2:29][CH2:30][NH:31][C:32]=3[N:23]=2)[CH2:3][CH2:4]1
Reactant: COc1ccc2nccc([C@@H](O)CN3CCC(N)CC3)c2n1
Reactant: O=Cc1ccc2c(n1)NCCC2
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc2nccc([C@@H](O)CN3CCC(NCc4ccc5c(n4)NCCC5)CC3)c2n1
Reaction time: 36 h
Yield: 83 %

Procedure:
To a stirred solution of (R)-2-(4-aminopiperidin-1-yl)-1-(6-methoxy-[1,5]naphthyridin-4-yl)ethanol (2f) (0.30 g, 1.0 mmole) in CH2Cl2 (25 mL) and dry ethanol (10 mL) at RT was added 5,6,7,8-tetrahydro-[1,8]naphthyridine-2-carboxaldehyde (prepared according to the procedure of WO 98/08840, 0.17 g, 1.0 mmole) and granular Na2SO4 (approximately 200 mg). After 36 h, the reaction was filtered through a sintered-glass funnel and the filtrate was concentrated. The remaining residue was dissolved in dry ethanol and reacted with NaBH4 (0.04 g, 1.0 mmole). After 12 h at RT, the reaction was concentrated under vacuum and the residue was dissolved in a mixture of H2O (2 mL) and saturated aqueous NaHCO3 (10 mL). The aqueous solution was extracted with EtOAc (2×50 mL) and the combined organic phases were washed with brine then were dried over Na2SO4. Flash chromatography on silica gel (9:1 CHCl3/MeOH containing 5% NH4OH) afforded the title compound (0.37 g, 83%) as a white solid:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[OH:22][CH2:23][CH2:24][NH2:25]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][NH:25][CH2:24][CH2:23][OH:22])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: OCCNCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
In analogy to example 3.1, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and Hydroxyethylamine were converted to yield 2-{3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propylamino}-ethanol as white semisolid, MS: 407 (MH+,1Br).
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]2[C:10]=1[C:11]([CH3:21])=[C:12]([CH3:20])[NH:13]2)C1C=CC=CC=1.C1CCCCC=1>[Pd].C(O)C>[CH3:20][C:12]1[NH:13][C:14]2[C:10]([C:11]=1[CH3:21])=[C:9]([OH:8])[CH:17]=[CH:16][C:15]=2[O:18][CH3:19]
Reactant: COc1ccc(OCc2ccccc2)c2c(C)c(C)[nH]c12
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: COc1ccc(O)c2c(C)c(C)[nH]c12

Procedure:
0.14 mole (39.5 g) of 4-benzyloxy-2,3-dimethyl-7-methoxyindole and 4 g of 10% palladium-on-charcoal in 120 ml of 96° ethanol to which has been added 80 ml of cyclohexene is heated under reflux. After 1 hour 30 minutes the catalyst is removed by hot filtration. The desired product is obtained by concentrating the filtrate to dryness. It is purified by dissolving it hot in isopropyl ether, filtering in the presence of charcoal and evaporating the filtrate to dryness. It melts at 164° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[C:4]2[C:10]3[CH2:11][CH2:12][CH2:13][C:9]=3[S:8][C:5]2=[N:6][CH:7]=1.CN(C)C1C=CC=CC=1.[F:30][C:31]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:32]=1[C:33](Cl)=[O:34]>ClCCl>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:3]1[C:2]([NH:1][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:38]([F:40])=[CH:39][C:31]=2[F:30])=[CH:7][N:6]=[C:5]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:4]=12
Reactant: Nc1cnc2sc3c(c2c1-c1ccccc1Cl)CCC3
Reactant: O=C(Cl)c1ccc(F)cc1F
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: O=C(Nc1cnc2sc3c(c2c1-c1ccccc1Cl)CCC3)c1ccc(F)cc1F
Reaction time: 0.17 h
Yield: 93.6 %

Procedure:
To a solution of 3-amino-4-(2-chlorophenyl)-6,7-dihydro-5H-cyclopenta[1',2':5,4]thieno[2,3-b]pyridine (150 mg) and N,N-dimethylaniline (0.065 ml) in dichloromethane (3 ml) was added dropwise 2,4-difluorobenzoyl chloride (0.07 ml) with ice-cooling. The mixture was stirred for 10 minutes with ice-cooling and then stirred at room temperature for 2 hours. Then, the mixture was washed in turn with water, aqueous saturated NaHCO3 solution and water, and dried over MgSO4The solvent was distilled off to obtain 4-(2-chlorophenyl)-3-(2,4-difluorobenzoylamino)-6,7 -dihydro-5H-cyclopenta[1',2':5,4]thieno[2,3-b]pyridine (206 mg, 93.6%) as crystals. The crystals were recrystallized from acetone to obtain colorless prisms, mp: 219°-220° C.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]=[C:5]=[O:6].[CH3:7][O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][NH2:12]>ClCCl>[CH3:7][O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][NH:12][C:5]1[O:6][CH2:2][CH2:3][N:4]=1
Reactant: O=C=NCCCl
Reactant: COc1ccccc1CN
Solvent: ClCCl
Product: COc1ccccc1CNC1=NCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
Commercially available 2-chloroethylisocyanate (3.10 mL, 36.45 mmol) was added slowly to a solution of 2-methoxybenzylamine (5.00 mL, 36.45 mmol) in dichloromethane (60 mL) at room temperature. The resulting reaction mixture was stirred for 30 minutes and the intermediate product thus formed was filtered and washed with hexane, and then suspended in water (150 mL). This suspension was heated to reflux and stirred at refluxing for 2 hours, then cooled to room temperature. The reaction mixture was extracted with ethyl acetate, and the aqueous phase was basified with ammonium hydroxide to pH=14. The basified aqueous phase was then extracted with ethyl ether (50 mL) 3 times and the combined organic phases were dried with magnesium sulfate. Concentration gave 5.10 g of N-(2-methoxybenzyl)-4,5-dihydrooxazol-2-amine. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ=3.80 (t, 2H, J=10.1 Hz), 3.85 (s, 3H), 4.26 (t, 2H, J=10.1 Hz), 4.38 (s, 2H), 6.83-6.95 (m, 2H), 7.20-7.32 (m, 2H).
Reaction SMILES: [Br:1][CH2:2]/[CH:3]=[CH:4]/[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1.[N+](=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N-]>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[Br:1][CH2:2][CH:3]1[CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=2)[CH:16]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: O=[N+]([O-])c1cccc(/C=C/CBr)c1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1C(CBr)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 66 h
Yield: 6.1 %

Procedure:
To a solution of 1-[(E)-3-bromo-1-propenyl]-3-nitrobenzene (Preparation 22, 820 mg, 3.23 mmol) in dichloromethane (3 ml) was added rhodium (II) acetate dimer (20 mg, 0.046 vmnol). To the mixture was added dropwise at room temperature over 3 h a solution of ethyl diazoacetate (0.47 ml, 510 mg, 4.47 mmol) in dichloromethane (3 ml), then the mixture was stirred at room temperature for 66 h. The mixture was purified by silica (100 g) column chromatography eluting with hexane:dichloromethane 100:0 to 50:50. Product containing fractions were combined and concentrated in vacuo to afford the title compound as a colourless oil (65 mg, 7%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:14][O:13]1.[C:15]([N:22]1[CH2:27][CH2:26][NH:25][C@H:24]([CH2:28][OH:29])[CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>C(O)C>[OH:29][CH2:28][C@H:24]1[N:25]([CH2:14][CH:12]([OH:13])[C:3]2[CH:4]=[CH:5][C:6]3[C:7](=[O:11])[O:8][CH2:9][C:10]=3[C:2]=2[CH3:1])[CH2:26][CH2:27][N:22]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:23]1
Reactant: Cc1c(C2CO2)ccc2c1COC2=O
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Solvent: CCO
Product: Cc1c(C(O)CN2CCN(C(=O)OC(C)(C)C)C[C@H]2CO)ccc2c1COC2=O
Temperature: 150 °C

Procedure:
4-Methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one (3.00 g, 15.8 mmol) and (S)-4-N-BOC-2-hydroxymethylpiperazine (5.12 g. 23.7 mmol) were suspended in ethanol (10 mL) in a 20 mL microwave tube. The reaction mixture was degassed and heated in a microwave apparatus for 30 min at 150° C. The reaction mixture was evaporated to dryness, then chromatographed through a 330 g Redi-sep column and eluted with a solvent system of 1:1 EtOAc/hexane to 100% EtOAc to yield the title compound. LC-MS: M+1=407.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[O:43]=[C:44]([N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1)[CH2:45][NH:46][C:47](=[O:61])[C:48]1[CH:53]=[CH:52][C:51]([O:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[CH:50][CH:49]=1>CN(C=O)C.O>[Cl:10][C:11]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:12]=1[C:13]([N:65]1[CH2:66][CH2:67][N:62]([C:44](=[O:43])[CH2:45][NH:46][C:47](=[O:61])[C:48]2[CH:49]=[CH:50][C:51]([O:54][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)=[CH:52][CH:53]=2)[CH2:63][CH2:64]1)=[O:15]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(Oc2ccccc2)cc1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccc(Cl)cc2Cl)CC1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
DIPEA (0.11 mL, 0.64 mmol) was added drop wise to 2,4-dichlorobenzoic acid (48 mg, 0.26 mmol) in DMF (5 mL). EDCI (102 mg, 0.53 mmol) and HOBT (34 mg, 0.26 mmol) were added consecutively. After 10 mins, N-(2-Oxo-2-piperazin-1-yl-ethyl)-4-phenoxy-benzamide hydrochloride (80 mg, 0.21 mmol) was added and the resulting mixture was stirred at room temperature overnight. Water was then added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification using column chromatography (silica gel of mesh size of 60-120 using 60:40 EtOAc:hexane as eluent) afforded N-{2-[4-(2,4-Dichloro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-4-phenoxy-benzamide: in 64% yield. LC-MS purity: 97%, 1H NMR (DMSO-D6): δ 8.5 (t, 1H), 7.9 (d, 2H), 7.7 (s, 1H), 7.5 (m, 4H), 7.2 (t, 1H), 7.1 (m, 4H), 4.2 (dd, 2H), 3.6 (m, 4H), 3.5 (m, 2H), 3.2 (m, 2H).
Reaction SMILES: [Cl-].[OH:2][CH2:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.[CH:30]([C:32]1[N:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]2)=[CH:34][CH:33]=1)=O.O1CCCC1.CC(C)([O-])C.[K+]>O>[OH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:30][C:32]2[N:37]=[CH:36][C:35]([N:38]3[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]3)=[CH:34][CH:33]=2)=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)nc2)CC1
Reactant: OCc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C=Cc3ccc(CO)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
To a mixture of [4-(hydroxymethyl)benzyl](triphenyl)phosphonium chloride (1.283 g, 3.064 mmol), tert-butyl 4-(6-formylpyridin-3-yl)piperazine-1-carboxylate (876.3 mg, 3.008 mmol) and anhydrous tetrahydrofuran (10 ml) was added potassium tert-butoxide (383.9 mg, 3.421 mmol), and the mixture was stirred at room temperature for 1 hr. Water (20 ml) was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1). The fraction containing the target product was concentrated and the obtained solid was dissolved in ethyl acetate, and extracted twice with 0.2M hydrochloric acid. The aqueous layer was saturated with sodium carbonate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give tert-butyl 4-(6-{2-[4-(hydroxymethyl)phenyl]vinyl}pyridin-3-yl)piperazine-1-carboxylate (850.2 mg, yield 71.5%, E/Z mixture) as a pale-yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:8]=[C:9]([C:13](=O)[CH2:14][CH2:15][C:16](=[O:18])[CH3:17])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1>[OH-].[Na+]>[F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:8]=[C:9]([C:13]3[CH2:14][CH2:15][C:16](=[O:18])[CH:17]=3)[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)CCC(=O)c1cccc(Oc2ccc(F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C1C=C(c2cccc(Oc3ccc(F)cc3)c2)CC1

Procedure:
A solution of 1-[3-(4-fluorophenoxy)phenyl]-1,4-pentanedione (19.03 g; 0.0665M) in 0.44M aqueous NaOH solution (300 ml) was refluxed for 24 hrs. After cooling, the residual solids were collected by filtration and dried to give 18 g (yield quant.) of the subtitle compound [D] as brown solids, which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8]([Cl:13])[N:7]=1)=[O:5])[CH3:2].Br[C:15]1[CH:16]=[N:17][CH:18]=[N:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>CC1C=CC=CC=1C.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH:12][C:15]2[CH:16]=[N:17][CH:18]=[N:19][CH:20]=2)=[CH:10][CH:9]=[C:8]([Cl:13])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Cl)ccc1N
Reactant: Brc1cncnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1nc(Cl)ccc1Nc1cncnc1
Temperature: 140 °C
Reaction time: 60 h

Procedure:
A suspension of 3-amino-6-chloro-pyridine-2-carboxylic acid ethyl ester (200 mg, 1.0 mmol), 5-bromopyrimidine (444 mg, 2.8 mmol), potassium carbonate (496 mg, 3.6 mmol) and water (76 μl, 4.4 mmol) in o-xylene was evacuated and vented with argon. Palladium(II) acetate (27 mg, 0.12 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos; 87 mg, 0.15 mmol) were added under argon and the reaction mixture was stirred at 140° C. for 60 h. After cooling down to ambient temperature, the reaction mixture was diluted with dichloromethane and the product was obtained after purification by silica gel chromatography using a heptane/ethyl acetate gradient as light yellow solid (98 mg, 35%).
Reaction SMILES: [C:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2)#[N:2].C(OOC(=O)C1C=CC=CC=1)(=[O:25])C1C=CC=CC=1.C([O-])(O)=O.[Na+]>ClC1C=CC=CC=1.C([O-])(=O)C1C=CC=CC=1.[Cu+2].C([O-])(=O)C1C=CC=CC=1>[C:1]([N:3]1[C:4]2[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=2[CH:6]([OH:25])[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2)#[N:2]
Reactant: N#CN1c2ccccc2CCc2ccccc21
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [Cu+2]
Agent: O=C([O-])O
Agent: O=C([O-])c1ccccc1
Solvent: Clc1ccccc1
Product: N#CN1c2ccccc2CC(O)c2ccccc21
Temperature: 50 °C
Reaction time: 5 h
Yield: 44.6 %

Procedure:
6.60 g (0.030 mols) of (I) are dissolved in 45 ml of chlorobenzene, heating to 50° C. under stirring, then added with 0.82 g (0.003 mols) of copper(II) benzoate and 6.9 g (0.033 mols) of dibenzoylperoxide. The reaction mixture is heated to 90° C. and stirred for 3 hours, then cooled to 40° C., added with 40 ml of a 3% HCI solution and stirred at 40° C. for 30 minutes, then at 80° C. for 5 hours. 20 ml of a NaHCO3 saturated solution are added to the mixture, which is stirred for 30 minutes and decanted for 1 hour The aqueous phase is separated and re-extracted with 8 ml of chlorobenzene. The combined organic phases are washed with water (10 ml), dried and concentrated at 60° C. to 20 ml, and 20 ml of hexane are added at this temperature. The mixture is cooled to 0-5° C. for 30 minutes and the solid is filtered to obtain 3.16 g (45%) of compound (VI), m.p. 112-3° C., with good purity.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C:8]([C:10]1[S:11][C:12]([S:35][CH3:36])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([N+:31]([O-])=O)=[CH:26][C:25]=3[Cl:34])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].CCO.[Cl-].[NH4+]>[Fe].O>[C:1]([O:5][C:6](=[O:37])[NH:7][C:8]([C:10]1[S:11][C:12]([S:35][CH3:36])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([NH2:31])=[CH:26][C:25]=3[Cl:34])[CH:21]=[CH:22][CH:23]=2)(=[O:16])=[O:17])[CH:14]=1)=[NH:9])([CH3:3])([CH3:4])[CH3:2]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc([N+](=O)[O-])cc2Cl)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(N)cc2Cl)c1
Temperature: 50 °C

Procedure:
{[4-(2′-Chloro-6′-methyl-4′-nitro-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (20 mg, 0.034 mmol, Example 134: step a) was dissolved into EtOH (2 mL). To this was added ammonium chloride (18 mg, 0.34 mmol) dissolved into water (4 mL). The reaction was heated to 50° C. and iron (9.6 mg, 0.34 mmol) was added. The reaction was then heated to 80° C. for 12 hours followed by filtration through celite with methanol and EtOAc. The solvents were removed in vacuo resulting in desired product that was used with out further purification or characterization.