Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13]Cl)=[CH:4][CH:3]=1.C1COCC1.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:51]([O-:54])(=[O:53])C.[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2].O>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][C:51]([OH:54])=[O:53])=[CH:4][CH:3]=1
Reactant: Fc1ccc(Cc2ccccc2CCl)cc1
Reactant: CC(=O)[O-]
Agent: [Pd+2]
Agent: [Na+]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1ccccc1Cc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 91 %

Procedure:
[2-(4-fluoro-benzyl)-phenyl]-chloromethane (1 eq.), THF (1 L/mol), water (0.7 L/mol), Pd(OAc)2 (1.3 mol %), dppp (2.6 mol %) and sodium acetate (2.5 eq.) were placed in a inertized reactor. The reaction mixture is placed under a CO pressure of 4 bars and allowed to stir at 80° C. for 20 hours. The organic layer is separated and evaporated under pressure. Toluene (0.75 L/mol) is added to the residue and the carboxylic acid is extracted with a 2 N solution of sodium hydroxide (0.75 L/mol). The black particles of palladium are removed by filtration over Celite. The water layer is placed in a flask and acetic acid (0.9 L/mol) is added. The mixture is warmed up to 80° C. then allowed to spontaneously cool down. The crystallisation starts around 50° C. The crystals are filtered off at room temperature, washed with water and dried to give black [2-(4-fluoro-benzyl)-phenyl]-acetic acid (91%). Treatment of 5 g of black [2-(4-fluoro-benzyl)-phenyl]-acetic acid with charcoal in 25 ml of a mixture of acetic acid and water (7/3) allows the isolation of pure white crystals of [2-(4-fluoro-benzyl)-phenyl]-acetic acid. This step can be performed before the first addition of acetic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1.[Cl:29][C:30]1[CH:31]=[N:32][NH:33][CH:34]=1.C(=NO)C1C(=CC=CC=1)O.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.O>[Cl:29][C:30]1[CH:31]=[N:32][N:33]([C:6]2[CH:5]=[CH:4][C:3]([N:9]3[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]4[N:22]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[N:21]=[CH:20][CH:19]=4)=[N:10]3)=[C:2]([F:1])[CH:7]=2)[CH:34]=1
Reactant: COc1cn(-c2ccc(I)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Reactant: Clc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: COc1cn(-c2ccc(-n3cc(Cl)cn3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Yield: 14.7 %

Procedure:
A suspension of 1-(2-fluoro-4-iodophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (488 mg, 1.0 mmol), 4-chloro-1H-pyrazole (103 mg, 1.0 mmol), Cu2O (14.3 mg, 0.1 mmol), salicylaldoxime (54.9 mg, 0.4 mmol), and Cs2CO3 (652 mg, 2.0 mmol) in CH3CN (10 mL) was refluxed overnight under Ar atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography eluting with AcOEt followed by purification by preparative HPLC. Recrystallization from MeOH/H2O gave the title compound (68.1 mg, 15% yield) as a pale yellow powder: mp 190-192° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.92 (3H, s), 6.43 (1H, t, J=9.0 Hz), 7.23 (1H, ddd, J=1.1, 2.3, 9.0 Hz), 7.35 (1H, d, J=1.9 Hz), 7.36-7.48 (5H, m), 7.57 (1H, dd, J=2.6, 12.4 Hz), 7.68 (1H, s), 7.79 (1H, d, J=1.9 Hz), 7.82 (1H, d, J=2.3 Hz), 7.92 (1H, d, J=0.8 Hz). LC-MS (ESI) m/z 463 [M+H]+. Anal. Calcd for C23H16ClFN6O2: C, 59.68; H, 3.48; N, 18.16. Found: C, 59.81; H, 3.50; N, 18.14.
Reaction SMILES: Br[C:2]1[C:3]([NH:18][C:19](=[O:32])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:8][CH2:7]2.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[CH2:62]=[CH:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>C(#N)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH:62]([C:2]1[C:3]([NH:18][C:19](=[O:32])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([C:28]([F:29])([F:31])[F:30])[CH:21]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([C:12](=[O:17])[C:13]([F:14])([F:15])[F:16])[CH2:8][CH2:7]2)=[CH:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1
Reactant: C=Cc1ccccc1
Reactant: COc1ccc(C(=O)Nc2ccc3c(c2Br)CN(C(=O)C(F)(F)F)CC3)cc1C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2ccc3c(c2C=Cc2ccccc2)CN(C(=O)C(F)(F)F)CC3)cc1C(F)(F)F
Yield: 83.9 %

Procedure:
A mixture of N-(8-bromo-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide (0.525 g), palladium diacetate (0.011 g), tris(o-tolyl)phosphine (0.03 g), triethylamine (0.15 g) and styrene (0.16 g) were combined in acetonitrile and warmed to reflux for 23 h. The mixture was cooled, partitioned between dichloromethane/water, the organic phase separated and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, ethyl acetate/hexane mixtures as eluant) to provide the title compound (0.46 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:16]([Sn](CCCC)(CCCC)CCCC)[CH:17]=[CH2:18]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([OH:15])([CH2:18][CH:17]=[CH2:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)C(=O)c1ccc(Cl)c(Cl)c1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: C=CCC(O)(C(=O)OCC)c1ccc(Cl)c(Cl)c1
Reaction time: 40 h
Yield: 77 %

Procedure:
To the solution of ethyl 2-(3,4-dichlorophenyl)-2-oxoacetate (100 g, 3.8 mol) in CH2Cl2 was added allyltributyltin (1.2 equivalents) and TiCl4 (1.2 equivalents) at 0° C. and mixture was stirred for 40 hours at 0° C. to room temperature. Purification by chromatography on silica gel provided title compound (90 g, 77%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH2:27]([NH2:29])[CH3:28]>C(#N)C>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:16]2[O:15][CH2:14][C@H:13]([CH2:12][NH:29][CH2:27][CH3:28])[O:18][C:17]=2[CH:19]=1)(=[O:24])=[O:25]
Reactant: CCN
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CCNC[C@H]1COc2ccc(S(C)(=O)=O)cc2O1
Temperature: 120 °C

Procedure:
A mixture of [(2R)-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (1.0 g, 2.51 mmol), ethanamine (2 ml, 70% in water) and ACN (6 ml) was heated under microwave radiation at 120° C. for 20 min. Purification on SCX-3 column (TEA/MeOH) and flash column chromatography (Isooctane/EtOAc/MeOH). Yield: 0.53 g, 78%. The amine was converted to the hydrochloric acid salt and crystallized from MeOH/Et2O. M.p. 271° C. MS m/z (rel. intensity, 70 eV) 271 (M+, 29), 58 (100), 59 (10), 272 (7), 79 (5). [α]=−66° (MeOH).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:13]1([CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CCOCC.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>[C:13]1([CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:2]2[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=[N:4][CH:3]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1cncc(Br)c1
Reactant: OB(O)c1ccccc1-c1ccccc1OCc1ccccc1
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: [K+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1cncc(-c2ccccc2-c2ccccc2OCc2ccccc2)c1
Temperature: 90 °C
Yield: 80.6 %

Procedure:
A mixture of ethyl 5-bromonicotinate (46 mg, 0.2 mmol), {2′-[(phenylmethyl)oxy]-2-biphenylyl}boronic acid (61 mg, 0.2 mmol), potassium carbonate (221 mg, 1.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol) was stirred and heated at 90° C. under nitrogen for 2 hours. After cooling the mixture was diluted with ether/water and the organic phase dried (magnesium sulphate), evaporated and chromatographed on silica eluting with ethyl acetate/iso-hexane (1:5) to give 66 mg of colourless gum.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5](/[CH:6]=[CH:7]/[C:8]([OH:10])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:35]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)([CH3:37])[CH3:36]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:6]=[CH:7]/[C:8]([N:41]2[CH2:42][CH2:43][N:38]([CH:35]([CH3:37])[CH3:36])[CH2:39][CH2:40]2)=[O:10])=[CH:11][CH:12]=1
Reactant: CC(C)N1CCNCC1
Reactant: O=C(O)/C=C/c1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)/C=C/c2ccc(F)cc2)CC1
Reaction time: 15.5 h
Yield: 73.2 %

Procedure:
To a solution of E-4-fluorocinnamic acid (1.18 g, 7. 10 mmol), which is commercially available from Sigma-Aldrich, and TBTU (3.42 g, 10.6 mmol) in DMF (50 mL) was added 1-isopropylpiperazine (1.12 mL, 7.81 mmol) at ambient temperature. The reaction was stirred for ca. 15.5 h before being concentrated under reduced pressure, wherein the crude residue was dissolved in EtOAc (70 mL) and partitioned with sat. aq. NaHCO3 (25 mL). The aq. layer was separated and further extracted with EtOAc (2×30 mL). The combined organic layers were then washed with sat. aq. NaHCO3 (2×20 mL) and brine (35 mL), then concentrated in vacuo. The resulting residue was subjected to flash chromatography (SiO2—40 g; gradient elution: 100% DCM for 5 min, then 0% to 2% MeOH/DCM over 5 min; hold for 5 min, 2% to 4% over 5 min, hold for 5 min, 4% to 10% over 5 min, hold 10% MeOH/DCM for 5 min at 40 mL/min) to give 1.58 g 10A (80% yield) as a pale orange solid. m/z (ES+) M+1=277.4; HPLC tR=1.50 min. 1H NMR (500 MHz, CDCl3) δ 7.62 (d, J=15.6 Hz, 1H), 7.50 (dd, J=8.9, 5.5 Hz, 2H), 7.11-6.99 (m, 2H), 6.80 (d, J=15.6 Hz, 1H), 3.85-3.54 (m, 4H), 2.73 (quintet, J=6.7 Hz, 1H), 2.55 (d, J=5.2 Hz, 4H), 1.05 (d, J=6.4 Hz, 6H).
Reaction SMILES: Br[CH2:2][C:3](=O)/[C:4](=[N:10]/[O:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([Cl:18])[CH2:14][CH2:13]1)/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:20][C:21]([NH2:23])=[S:22]>>[NH2:23][C:21]1[S:22][CH:2]=[C:3](/[C:4](=[N:10]/[O:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([Cl:18])[CH2:14][CH2:13]2)/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:20]=1
Reactant: CCOC(=O)/C(=N\O[C@H]1CC[C@H](Cl)CC1)C(=O)CBr
Reactant: NC(N)=S
Product: CCOC(=O)/C(=N\O[C@H]1CC[C@H](Cl)CC1)c1csc(N)n1

Procedure:
Ethyl 4-bromo- (Z)-2-(trans-4-chlorocyclohexyloxyimino)-3-oxobutyrate (730 mg) was treated with thiourea as described in Example 4d, to give the title compound (579 mg, 85%) m.p. 155° C. (ethyl acetate-hexane) (Found: C, 47.05; H, 5.02; N, 12.75; Cl, 10.8; S, 9.73. C13H18N3CLO3S requires C,47.1; H, 5.4; N, 12.7; Cl, 10.7; S, 9.7%). νmax (Nujol) 3450, 3430, 3250, 3125, 1720, 1615, 1610, and 1540 cm-1, νH (CDCl3), 1.36 (3H, t, J 7.1 Hz), 1.73 (4H, m), 2.13 (4H, m), 4.18 (1H, m), 4.39 (2H, q, J 7.1 Hz), latter signal obscures single hydrogen multiplet, 5.5 (2H, s, exch. D2O), and 6.71 (1H, s).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=3)[C:14]([NH:16][CH3:17])=[O:15])=[CH:10][C:5]2=[N:4][CH:3]=1.[N:21]1([C:26]2[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=2)[CH:25]=[CH:24][CH:23]=[N:22]1.O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:17][NH:16][C:14](=[O:15])[C:13]1[CH:18]=[CH:19][CH:20]=[C:11]([C:9]2[CH:8]=[CH:7][N:6]3[C:2]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([N:21]5[CH:25]=[CH:24][CH:23]=[N:22]5)[CH:31]=4)=[CH:3][N:4]=[C:5]3[CH:10]=2)[CH:12]=1
Reactant: OB(O)c1cccc(-n2cccn2)c1
Reactant: CNC(=O)c1cccc(-c2ccn3c(Br)cnc3c2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CNC(=O)c1cccc(-c2ccn3c(-c4cccc(-n5cccn5)c4)cnc3c2)c1

Procedure:
3-(3-Bromo-imidazo[1,2-a]pyridine-7-yl)-N-methyl-benzamide (Intermediate EA) (1 eq, 0.303 mmol, 100 mg) and 3-(1H-pyrazolyl)-phenylboronic acid (1.3 eq, 0.394 mmol, 74 mg) are dissolved in DME (3 ml) and water (0.8 ml) and Na2CO3 (3 eq, 0.909 mmol, 96.3 mg) is added. PdCl2(PPh3)2 (0.05 eq, 0.015 mmol, 10.6 mg) is added and the reaction mixture is heated using microwave radiation at 120° C. for 10 min. At the completion of this time the solvent is removed in vacuo and the reaction mixture is purified by flash column chromatography eluting with 9:1 DCM/MeOH to yield N-methyl-3-[3-(3-pyrazol-1-yl-phenyl)-imidazo[1,2-a]pyridin-7-yl]-benzamide as a light brown solid; [M+H]+=395
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Al](Cl)(C)C.[CH3:13][N:14]([CH3:39])[C:15]([C:17]1[N:22]=[CH:21][C:20]([O:23][C:24]2[C:29]3[CH:30]=[C:31]([CH3:33])[O:32][C:28]=3[CH:27]=[C:26]([C:34](OCC)=[O:35])[CH:25]=2)=[CH:19][N:18]=1)=[O:16].CC1CCCO1>COC.O>[CH3:39][N:14]([CH3:13])[C:15]([C:17]1[N:22]=[CH:21][C:20]([O:23][C:24]2[C:29]3[CH:30]=[C:31]([CH3:33])[O:32][C:28]=3[CH:27]=[C:26]([C:34](=[O:35])[NH:8][C:5]3[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=3)[CH:25]=2)=[CH:19][N:18]=1)=[O:16]
Reactant: CCOC(=O)c1cc(Oc2cnc(C(=O)N(C)C)nc2)c2cc(C)oc2c1
Reactant: Cc1cnc(N)cn1
Agent: COC
Agent: C[Al](C)Cl
Solvent: CC1CCCO1
Solvent: O
Product: Cc1cnc(NC(=O)c2cc(Oc3cnc(C(=O)N(C)C)nc3)c3cc(C)oc3c2)cn1
Temperature: 25 °C

Procedure:
To a solution of the 5-methyl-2-aminopyrazine (38.9 g, 356 mmol) in dimethylether (315 mL) in a 3-neck flask equipped with overhead stirring and a condensor at 0° C. was added Me2AlCl (1M solution in hexanes) (715 mL). The mixture was warmed at room temperature and stirred for 1.5 hours. In a separate flask, ethyl 4-(2-(dimethylcarbamoyl)pyrimidin-5-yloxy)-2-methylbenzofuran-6-carboxylate (1-2a: 52.6 g, 142.5 mmol) was dissolved in dimethylether (210 mL). This mixture was then added to the complexed amine. A gum precipitated upon scratching the flask and dissipated into a solid. The resultant reaction was refluxed for 3.5 hours HPLC indicated 93% complete. Five liters of Rochelles salt made up in water and 2 liters of 2-methyltetrahydrofuran was added to the mixture. The reaction mixture was then poured into the biphasic system. The mixture was allowed to stir with overhead stirring for 14 hours, after which time, a yellow solid precipitated. The solid was collected through filteration. The solid retained was washed with 2-methyltetrahydrofuran. The resultant solid was dried in vacuo oven overnight to afford the title compound N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide (2): (49.98 g, 81%)
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]1([CH2:18][C:19]([OH:21])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[O:22]1[CH:27]=[CH:26][CH2:25][CH2:24][CH2:23]1.C(N(CC)CC)C>ClCCl>[C:12]1([CH2:18][C:19]([O:21][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][O:22]2)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)OC1CCCCO1

Procedure:
To a saturated solution of anhydrous p-toluenesulphonic acid in dry dichloromethane (25 ml), phenylacetic acid (E4) (0.581 g, 4.26 mmol) and 3,4-dihydro-2H-pyran (3 ml, 32.9 mmol) were successively added, and the resultant solution was stirred for 1 hour at room temperature. To the reaction mixture, triethylamine (1 ml, 7.2 mmol) was added, and the volatiles were evaporated. The crude title compound was obtained and was immediately utilized in the next step of the synthesis.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15](O)=O.N>>[CH:1]1([CH2:7][CH2:8][NH:9][CH2:15][C:11]2[O:10][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccco1
Reactant: NCCC1CCCCC1
Agent: N
Product: c1coc(CNCCC2CCCCC2)c1

Procedure:
The desired amine was prepared using the method described in Example 1171A starting with cyclohexylethylamine and 2-furoic acid. m/e (DCI/NH3) 208 (MH+)
Reaction SMILES: COC1C=CC([CH2:7][C:8]([O:13][C:14](=[O:30])[C@H:15]([CH:27]([CH3:29])[CH3:28])[NH:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])(C)[C:9]([O-:11])=[O:10])=CC=1.FC(F)(F)C(O)=O>ClCCl>[C:17]([NH:16][C@H:15]([C:14]([O:13][CH:8]([CH3:7])[C:9]([OH:11])=[O:10])=[O:30])[CH:27]([CH3:28])[CH3:29])([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]
Reactant: COc1ccc(CC(C)(OC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)C(=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(OC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-methoxybenzyl-2-(N-CBZ-L-valyloxy)-propionate (7.8 g, 17.5 mmole) in dichloromethane (100 ml) was added trifluoroacetic acid (10 ml) and the solution was stirred for one hour at room temperature. The solution was evaporated under reduced pressure and the product was isolated by silica gel column chromatography. Yield: 5.0 g
Reaction SMILES: C([Li])CCC.CCCCCC.[CH2:12]([C@H:19]1[CH2:23][O:22][C:21](=[O:24])[NH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30].[Cl-].[NH4+]>O1CCCC1>[CH2:12]([C@H:19]1[CH2:23][O:22][C:21](=[O:24])[N:20]1[C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH3:25])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCCCC(=O)Cl
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 0.33 h
Yield: 101.2 %

Procedure:
90 ml of a solution of n-butyllithium in n-hexane (1.60 mol/l) (144 mmol) was added to a solution of 25.0 g of (S)-4-benzyl-2-oxazolidinone (141 mmol) in tetrahydrofuran (600 ml) under a nitrogen atmosphere and at −78° C. over 10 minutes, and the mixture was stirred at the same temperature for 20 minutes. Then, 19.0 ml of n-valeryl chloride (159 mmol) was added over 10 minutes. The mixture was stirred at the same temperature for 20 minutes and then further stirred at room temperature for three hours. 90 ml of a saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was further stirred at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure and diluted with 300 ml of water, followed by extraction with methylene chloride. Then, the organic layer was washed with a saturated sodium bicarbonate aqueous solution and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain 37.3 g of the crude title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=CC=2)[CH:3]=[CH:2]1.C([N:17]1[C:29]2[C:28]([OH:30])=[C:27]3[N:31](C(OC(C)(C)C)=O)[C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Cl:46])[CH:22]=2)(OC(C)(C)C)=O.C(N1CCC(CO)CC1)(OC(C)(C)C)=O>>[Cl:38][C:35]1[CH:36]=[C:37]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:27]1[C:28]([O:30][CH2:6][CH:5]3[CH2:3][CH2:2][NH:1][CH2:9][CH2:4]3)=[C:29]3[NH:17][C:18]4[CH:19]=[CH:20][C:21]([Cl:46])=[CH:22][C:23]=4[C:24]3=[CH:25][C:26]2=1
Reactant: CC(C)(C)OC(=O)n1c2ccc(Cl)cc2c2cc3c4cc(Cl)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Reactant: c1ccc2[nH]ccc2c1
Agent: CC(C)(C)OC(=O)N1CCC(CO)CC1
Product: Clc1ccc2[nH]c3c(OCC4CCNCC4)c4[nH]c5ccc(Cl)cc5c4cc3c2c1

Procedure:
The title compound was prepared in a manner analogous to Example 28 except the starting indole is 5,7-diBOC-2,10-dichloro-6-hydroxyindolo[2,3-b]carbazole and the reagent is N-Boc-4-piperidinemethanol. 1H-NMR (400 MHz, CD3OD) δ ppm 8.43 (s, 1H), 8.11 (d, J=2.0 Hz, 2 H), 7.43 (d, J=8.8 Hz, 2 H), 7.29 (dd, J=8.4, 2.0 Hz, 2 H), 4.16 (d, J=6.4 Hz, 2 H), 3.18-3.08 (m, 2 H), 2.70 (td, J=12.4, 2.4 Hz, 2 H), 2.22-2.10 (m, 1 H), 2.09-1.98 (m, 2 H), 1.50-1.38 (m, 2 H); MS (ESI) m/z 436.2 (M−H)−; MS (ESI) m/z 438.1 (M+H)+
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[F:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:19]=1[CH:20]=O.O>O1CCCC1>[F:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:19]=1/[CH:20]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1ccc(C=O)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc(OC)cc1F
Reaction time: 0.25 h
Yield: 97.3 %

Procedure:
To a solution of ice-cooled ethyl diethylphosphonoacetate (9.45 g, 42.1 mmol) in tetrahydrofuran (50 mL) was added sodium hydride (60% in oil, 1.54 g, 38.5 mmol) and the mixture was stirred for 15 min. A solution of 2-fluoro-4-methoxybenzaldehyde (5.00 g, 32.4 mmol) in tetrahydrofuran (30 mL) was added dropwise. The mixture was stirred at room temperature for 2 hr, and water was added. The mixture was extracted with ethyl acetate. The extract washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane) to give the title compound (7.07 g, yield 97%) as a colorless oil. 1H NMR (CDCl3) δ: 1.33 (3H, t, J=7.1 Hz), 3.83 (3H, s), 4.26 (2H, q, J=7.1 Hz), 6.41 (1H, d, J=16.2 Hz), 6.61-6.73 (2H, m), 7.45 (1H, t, J=8.6 Hz), 7.75 (1H, d, J=16.2 Hz).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:16]([OH:18])=[O:17])[CH:10]=[CH:9]2)(=[O:3])[CH3:2].[CH3:19]N(N=O)C(N)=O.[OH-].[K+].CC(O)=O>CCOCC>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:16]([O:18][CH3:19])=[O:17])[CH:10]=[CH:9]2)(=[O:3])[CH3:2]
Reactant: CN(N=O)C(N)=O
Reactant: CC(=O)OCc1ccc2cc(C(=O)O)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)c1ccc2cc(COC(C)=O)ccc2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 139.8 %

Procedure:
To a suspension of 1.08 g (4.43 mmol) of 6-acetoxymethyl-2-naphthoic acid in 150 mL of Et2O at 0° C. was added a cold solution of CH2N2 in Et2O which was prepared from 2.0 g (19 mmol) of N-methyl-N-nitrosourea and 30 mL of 40% aqueous KOH. The mixture was stirred at 0° C. for 10 min when all the solid went into solution. Excess CH2N2 was decomposed with HOAc. The reaction mixture was dried over Na2SO4 and concentrated to give 1.6 g of a white solid, which was purified on 100 g of silica gel (50% EtOAc/hexane) to give 1.04 g (91% yield) of the pure methyl ester. A portion was recrystallized from EtOAc/hexane to give white plates: mp 115°-116° C.; IR (mull) 1720, 1300, 1260, 1200, 1140, 1100, 1040, 980, 940, 900, 840, 820, 760 cm-1 ; 1 H NMR (CDCl3) δ2.15 (s, 3, CH3CO2), 3.98 (s, 3, CO2CH3), 5.28 (s, 2, CH2O), 7.3-8.7 (m, 6, ArH); MS calcd for C15H14O4 258.0892, found 258.0872.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12](Cl)=[O:13])[CH:6]=[CH:5]2.[NH2:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH:21]([CH2:26][OH:27])[CH2:22][NH:23]2)=[CH:18][CH:17]=1>>[OH:27][CH2:26][CH:21]1[CH2:20][C:19]2[C:24](=[CH:25][C:16]([NH:15][C:12]([C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=4)[CH:8]=3)=[O:13])=[CH:17][CH:18]=2)[NH:23][CH2:22]1
Reactant: O=C(Cl)c1ccc2cc(Br)ccc2c1
Reactant: Nc1ccc2c(c1)NCC(CO)C2
Product: O=C(Nc1ccc2c(c1)NCC(CO)C2)c1ccc2cc(Br)ccc2c1

Procedure:
This material was prepared analogous to the procedure described for Example 1(c). 6-Bromo-naphthalene-2-carbonyl chloride, Example 2(a), (258 mg, 0.96 mmol) reacted with (7-amino-1,2,3,4-tetrahydro-quinolin-3-yl)-methanol (171 mg, 0.96 mmol, prepared according to the procedure described in WO03049702) to give the title compound as an light-brown amorphous solid. MS (ESI, pos. ion) m/z: 413 (M+1).