Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=CC(CN2C(=O)C(COS(C)(=O)=O)=CC(C3C=CC4OCCC=4C=3)=N2)=CC=1.[O:31]1[C:35]2[CH:36]=[CH:37][C:38]([C:40]3[CH:41]=[C:42]([C:47]([O:49]C)=[O:48])[C:43](=[O:46])[NH:44][N:45]=3)=[CH:39][C:34]=2[CH2:33][CH2:32]1.[Cl:51][C:52]1[CH:59]=[CH:58][C:55]([CH2:56]Cl)=[CH:54][CH:53]=1>>[C:47]([C:42]1[C:43](=[O:46])[N:44]([CH2:56][C:55]2[CH:58]=[CH:59][C:52]([Cl:51])=[CH:53][CH:54]=2)[N:45]=[C:40]([C:38]2[CH:37]=[CH:36][C:35]3[O:31][CH2:32][CH2:33][C:34]=3[CH:39]=2)[CH:41]=1)([OH:49])=[O:48]
Reactant: ClCc1ccc(Cl)cc1
Reactant: COC(=O)c1cc(-c2ccc3c(c2)CCO3)n[nH]c1=O
Agent: CS(=O)(=O)OCc1cc(-c2ccc3c(c2)CCO3)nn(Cc2ccc(F)cc2)c1=O
Product: O=C(O)c1cc(-c2ccc3c(c2)CCO3)nn(Cc2ccc(Cl)cc2)c1=O
Yield: 89.3 %

Procedure:
The general procedure of Example 1 (3) was carried out by use of 6-(2,3-dihydro-1-benzofuran-5-yl)-4-methoxycarbonyl-2H-pyridazin-3-one and 4-chlorobenzyl chloride, to thereby yield the title compound as a yellow powder (yield: 89.3%).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH:15]=2)[C:10]([Br:27])=[N:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:20]([O:19][C:17]([C:14]1[CH:15]=[C:16]2[C:11]([C:10]([Br:27])=[N:9][NH:8]2)=[CH:12][CH:13]=1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)n1nc(Br)c2ccc(C(=O)OCc3ccccc3)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCc1ccccc1)c1ccc2c(Br)n[nH]c2c1

Procedure:
A solution of 3-bromo-indazole-1,6-dicarboxylic acid 6-benzyl ester 1-tert-butyl ester (2.05 g, 4.75 mmol) and TFA (3.66 mL, 47.5 mmol) in CH2Cl2 (30 mL) was stirred at RT for 16 h. A saturated aqueous solution of NaHCO3 was added, the layers were separated and the aqueous layer was extracted with CH2Cl2 (×3). The combined organic extracts were dried (Na2SO4), filtered and concentrated and the material thus obtained was used without further purification in the next step. MS (UPLC/MS): 331.2/333.2 [M+H]+, 329.3/331.2 [M−H]−; tR (UPLC conditions m): 1.18 min.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[N:16]=[CH:15][C:14]([C:17]2[N:26]([C:27]3[CH:32]=[CH:31][C:30]([CH:33]([CH2:35][CH3:36])[CH3:34])=[CH:29][CH:28]=3)[C:25](=[O:37])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)=[CH:13][CH:12]=1>C([O-])([O-])=O.[Na+].[Na+].COCCOC.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>[CH:33]([C:30]1[CH:31]=[CH:32][C:27]([N:26]2[C:25](=[O:37])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[C:17]2[C:14]2[CH:15]=[N:16][C:11]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:12][CH:13]=2)=[CH:28][CH:29]=1)([CH2:35][CH3:36])[CH3:34]
Reactant: CCC(C)c1ccc(-n2c(-c3ccc(Br)nc3)nc3ccccc3c2=O)cc1
Reactant: OB(O)c1ccccc1
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: COCCOC
Product: CCC(C)c1ccc(-n2c(-c3ccc(-c4ccccc4)nc3)nc3ccccc3c2=O)cc1
Yield: 34.1 %

Procedure:
Phenylboronic acid (0.041 g, 0.34 mmol) and Pd(PPh3)4 (0.003 g) were added to a mixture of 2-(6-bromopyridin-3-yl)-3-(4-sec-butylphenyl)quinazolin-4(3H)-one (0.150 g, 0.34 mmol) in 2 M Na2CO3 (0.3 mL) and DME (5 mL). After refluxing overnight, the reaction mixture was concentrated in vacuo. The residue was dissolved in CHCl3 and washed with H2O, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 0% to 20% of EtOAc in CH2Cl2, afforded the title compound as a white solid (0.050 g, 34%). 1H-NMR (300 MHz, DMSO-d6): δ8.63 (s, 1H), 8.22 (d, J=7.0 Hz, 1H), 7.90-8.06 (m, 3H), 7.76-7.88 (m, 3H), 7.60-7.73 (m, 1H), 7.40-7.54 (m, 3H), 7.27-7.36 (m, 2H), 7.13-7.22 (m, 2H), 2.52-2.65 (m, 1H), 1.34-1.59 (m, 2H), 1.12 (d, J=6.9 Hz, 3H), 0.56 (t, J=7.3 Hz, 3H). MS (APCI) m/z: 432 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:21][CH2:20][CH2:19][C@H:18]([N:22]([CH2:29][C:30]3[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=3)[C:23]3[N:24]=[N:25][N:26]([CH3:28])[N:27]=3)[C:17]3[CH:44]=[C:45]([CH3:52])[C:46]([C:48]([F:51])([F:50])[F:49])=[CH:47][C:16]2=3)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.O>[F:39][C:36]([F:37])([F:38])[C:34]1[CH:35]=[C:30]([CH:31]=[C:32]([C:40]([F:41])([F:42])[F:43])[CH:33]=1)[CH2:29][N:22]([C@H:18]1[CH2:19][CH2:20][CH2:21][N:15]([CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:16]2[CH:47]=[C:46]([C:48]([F:49])([F:50])[F:51])[C:45]([CH3:52])=[CH:44][C:17]1=2)[C:23]1[N:24]=[N:25][N:26]([CH3:28])[N:27]=1
Reactant: Cc1cc2c(cc1C(F)(F)F)N(CC1CCN(C(=O)OC(C)(C)C)CC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)N(CC1CCNCC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl}-piperidine-1-carboxylic acid tert-butyl ester (0.09) in dichloromethane (10 mL), add trifluoroacetic acid (2 mL). After stirring for 1 h at room temperature, quench the reaction with concentrated sodium carbonate (10 mL) and dilute with dichloromethane (20 mL) and water (20 mL). Separate the organics and wash the aqueous with dichloromethane (2×10 mL). Dry the combined organics over sodium sulfate, filter, and remove solvent under vacuum. Chromatograph the reaction over silica gel eluting with methanol/dichloromethane (0-5%) to afford the title compound as a colorless foam. MS (ES+): 650 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].O=[C:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]#[N:17].[Cl-].[Ca+2].[Cl-]>>[F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:11]1[CH2:15][CH2:14][CH2:13][C:12]=1[C:16]#[N:17]
Reactant: Nc1ccc(F)cc1F
Reactant: N#CC1CCCC1=O
Agent: [Ca+2]
Agent: [Cl-]
Product: N#CC1=C(Nc2ccc(F)cc2F)CCC1

Procedure:
2,4-Difluoro-aniline (2.6 g, 20.0 mmol) (Aldrich Chemicals) cyano-ketone (Example 11) (2.2 g, 20.2 mmol), calcium chloride (2.5 g, 22.5 mmol) and T.H.F. (30 ml) were heated under reflux for 19 hours. After cooling, the mixture was filtered and the solvent evaporated. Kugelrohr distillation (125° C., 0.25 mmHg) gave the product as pale yellow crystals.
Reaction SMILES: [CH2:1]([N:4]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[C:8]([NH2:17])[CH:9]=2)[CH2:2][CH3:3].[C:18]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:35])[CH2:28][CH:29]([CH3:34])[CH2:30][C:31](O)=[O:32])=[CH:22][CH:21]=1)#[N:19].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:18]([C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:35])[CH2:28][CH:29]([CH3:34])[CH2:30][C:31]([NH:17][C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]([CH2:1][CH2:2][CH3:3])[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]3=2)=[O:32])=[CH:24][CH:25]=1)#[N:19]
Reactant: CC(CC(=O)O)CC(=O)Nc1ccc(C#N)cc1
Reactant: CCCn1c2c(c3cc(N)ccc31)CCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCn1c2c(c3cc(NC(=O)CC(C)CC(=O)Nc4ccc(C#N)cc4)ccc31)CCCC2
Temperature: 25 °C
Reaction time: 14 h
Yield: 33.2 %

Procedure:
To a solution of the compound obtained in Step 2 (229 mg, 1.00 mmol), 5-(4-cyanophenylamino)-3-methyl-5-oxopentanoic acid (247 mg, 1.00 mmol) and DIEA (0.525 mL, 3.01 mmol) in DMF (6 mL) was added HATU (572 mg, 1.50 mmol), and the mixture was stirred at room temperature for 14 hr. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5 to 75% ethyl acetate/hexane) to give the title compound (151 mg, 0.332 mmol, 33.1%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1.N1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19].O>O1CCCC1>[S:8]1[C:4]2[CH:3]=[C:2]([NH:1][C:18](=[O:19])[O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])[CH:10]=[CH:9][C:5]=2[N:6]=[CH:7]1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1ccc2ncsc2c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc2ncsc2c1)OCC(Cl)(Cl)Cl

Procedure:
To a solution of 6-amino-1,3-benzothiazole (1.00 g, 6.66 mmol) and pyridine (0.633 ml, 7.99 mmol) in tetrahydrofuran (22 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (1.11 ml, 7.99 mmol), and the mixture was stirred at room temperature for 1.5 hour. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was poured to the residue, and 1.45 g (66.7%) of the desired product as a solid was separated by filtration.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][CH2:6][C:7](Cl)=[O:8].[F:10][C:11]([F:25])([F:24])[C:12]([N:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15]1)=[O:13]>C(Cl)Cl>[Cl:5][CH2:6][C:7]([C:18]1[CH:17]=[C:16]2[C:21]([CH2:22][CH2:23][N:14]([C:12](=[O:13])[C:11]([F:10])([F:25])[F:24])[CH2:15]2)=[CH:20][CH:19]=1)=[O:8]
Reactant: O=C(N1CCc2ccccc2C1)C(F)(F)F
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCl)c1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
To a suspension of AlCl3 (24.16 g) in CH2Cl2 (162 ml) was added chloroacetyl chloride (15 ml) dropwise at 0-5° C. under argon for 20 min and left to warm to room temperature. To this mixture was added compound (4) (9.29 g, 40 mmol) over a period of 30 min at room temperature. The resulting mixture was then stirred for an additional 3 hours and poured onto a mixture of ice-cold water (407 ml). The mixture was stirred for 5 min, and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×200 ml). The combined organic layers were washed with water (2×240 ml) and 5% aqueous NaHCO3 (3×240 ml). The organic layer was dried and the solvent evaporated to give a white solid (5) (10.47 g, 88%). TLC Rf=0.4 (n-hexane/EtOAc=3:1). mp: 120-122° C. 1H NMR (300 MHz, CDCl3) (NMR, Varian Gemini): δ 7.78 (q, J=4 Hz, 1H, Aryl H), 7.34-7.26 (m, 2H, Aryl Hs), 4.87 (s, 2H, Ph-CH2—N), 4.67 (s, 2H, —CH2—C═O), 3.95-3.87 (m, 2H, —CH2—N), 3.06-3.01 (m, 2H, Ph-CH2—)—. Fast Atom Bombardment Mass Spectrometry (FABMS) m/z: 306 (M+1) (C13H11NO2ClF3).
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)=O>>[Cl:25][C:20]1[CH:19]=[C:18]([C:16]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=3[CH3:8])[S:13][CH:15]=2)[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Reactant: O=C(CBr)c1ccc(Cl)c(Cl)c1
Product: COC(=S)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)c(C)s1
Yield: 94.7 %

Procedure:
176 mg (0.712 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was reacted with 2-bromo-3′,4′-dichloroacetophenone (0.854 mmol; 330 mg) in a manner similar to Example 22, step (a) to afford 270 mg (91% yield) of methyl 4-[4-(3,4-dichlorophenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:9][C:10]1[C:11]([CH3:20])=[C:12]2[C:16](=[CH:17][CH:18]=1)[CH:15]([OH:19])[O:14][CH2:13]2.N1C=CN=C1>C(Cl)Cl>[Br:9][C:10]1[C:11]([CH3:20])=[C:12]2[C:16](=[CH:17][CH:18]=1)[CH:15]([O:19][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[O:14][CH2:13]2
Reactant: Cc1c(Br)ccc2c1COC2O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: Cc1c(Br)ccc2c1COC2O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of TBS-Cl (3.63 g, 24.10 mmol) in methylene chloride (15 mL) was added to a solution of 5-bromo-4-methyl-1,3-dihydroisobenzofuran-1-ol (2.76 g, 12.1 mmol) and imidazole (1.72 g, 25.3 mmol) in methylene chloride (80 mL) at 0° C., the resulting solution was stirred at rt overnight. The mixture was partitioned between DCM and water, the water phase was extracted with methylene chloride and the combined organic phase was dried over sodium sulfate then concentrated, and the residue was purified on silica gel column using ethyl acetatehexane to give the title compound. LC/MS: (M−131)+: 210.91; 212.91.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][CH2:15][CH:16]1[NH:21][C:20](=O)[CH2:19][NH:18][C:17]1=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([O:14][CH2:15][CH:16]1[CH2:17][NH:18][CH2:19][CH2:20][NH:21]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1CNC(=O)C(COCc2ccccc2)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(COCC2CNCCN2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
A 250 ml, round-bottomed flask was charged with lithium aluminum hydride (1.871 g, 49.3 mmol) and THF (75 mL). After cooling to 0° C., 3-(benzyloxymethyl)piperazine-2,5-dione (3.85 g, 16.44 mmol) was slowly added. The mixture was warmed to room temperature and then heated at reflux for 1 h. After this time, the mixture was cooled to 0° C. and the reaction was quenched with sodium sulfate decahydrate (20 g) and stirred vigorously for 1 h. The mixture was filtered, and the filtrate was concentrated to give 2-(benzyloxymethyl)piperazine (2.60 g) as a yellow oil. This material was taken to the next step without purification.
Reaction SMILES: [C:1]([C:9]1[CH:13]=[CH:12][O:11][C:10]=1[CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>[Pd]>[CH:1](/[C:9]1[CH:13]=[CH:12][O:11][C:10]=1[CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:2]/[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC#Cc1ccoc1C=C(C(=O)OCC)C(=O)OCC
Agent: [Pd]
Product: CCCCCC/C=C\c1ccoc1C=C(C(=O)OCC)C(=O)OCC
Yield: 80.4 %

Procedure:
Diethyl 2-[3-(1-octynyl)-2-furanylmethylene]propan-1,3-dioate(1.04 g, 3 mmole from example 16) was hydrogenated over 5% palladium on barium sulphate as described in Example 12 to yield, after chromatography on silica (DCM:Hexane 1:1) the title compound 0.84 g (80%) as an oil, νmax (film) 1740, 1720, 1610, 1025, 885, 865, 760; δ(CDCl3) 0.88(3H, distorted t), 1.32(3H, t, J=7 Hz), 1.34(8H, m), 1.37(3H, t, H=7 Hz), 2.26(2H, m), 4.28(2H, q, J=7 Hz), 4.40(2H, q, J=7 Hz), 5.8(1H, m), 6.33(1H, m), 6.6(1H, d, J=2 Hz), 7.45(1H, d, J=2 Hz), 7.49(1H, s).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]2[O:24][CH:23]=[C:22](Br)[C:15]=2[CH:16]=[N:17][C:18]=1[N+:19]([O-:21])=[O:20])[CH3:11].CC1(C)C(C)(C)OB([C:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH:35]=2)O1.C(=O)([O-])[O-].[K+].[K+]>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.O1CCOCC1.O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]2[O:24][CH:23]=[C:22]([C:34]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH:35]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[N+:19]([O-:21])=[O:20])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC(Oc1c([N+](=O)[O-])ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(Oc1c([N+](=O)[O-])ncc2c(C3=CCN(C(=O)OC(C)(C)C)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 92.5 °C

Procedure:
A mixture of 7-(1-(2,6-Dichloro-3-fluorophenyl)ethoxy)-3-bromo-6-nitrofuro[3,2-c]pyridine (12.6 g, 28.1 mmol), tert-butyl 5,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-1(2H)-carboxylate (9.56 g, 30.9 mmol) and dioxane/water (4:1, 120 mL/30 mL) in a 500-mL round-bottom flask was stirred and degassed with nitrogen for 15 min. To the solution, Pd(PPh3)2Cl2 (400 mg, 0.57 mmol) was added followed by potassium carbonate (5.82 g, 42.19 mmol) was added and degassed with nitrogen for another 5 min. The mixture was heated at 90-95° C. for 2.5 h. TLC (5% methanol in dichloromethane) indicated completion of the reaction. The mixture was cooled to RT, and solvent was removed on rotary evaporator. To the residue, water (60 mL) and dichloromethane (150 mL) were added. The organic layer was separated and the aqueous layer was extracted with dichloromethane (2×60 mL). All organic layers were combined and washed with brine solution (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 1:1 ethyl acetate and dichloromethane to give the title compound. 1H NMR (CDCl3, 300 MHz): δ=1.45 (s, 9H), 1.95 (d, J=6.6 Hz, 3H), 2.45 (brs, 2H), 3.62 (t, J=6.0 Hz, 2H), 4.18 (t, J=3.0 Hz, 2H), 6.25 (brs, 1H), 6.63 (t, J=6.0 Hz, 1H), 7.05 (m, 1H), 7.21 (m, 1H), 7.69 (s, 1H), 8.60 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([C:12]([O:14][CH3:15])=[O:13])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C>[Br:16][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[F:1])[O:9][CH2:8][CH2:7][CH:6]2[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C1CCOc2cc(F)ccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1CCOc2cc(F)c(Br)cc21
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 89.7 %

Procedure:
Methyl 7-fluoro-3,4-dihydro-2H-chromene-4-carboxylate (336 mg, 1.60 mmol) was diluted with DMF (5 mL) followed by the addition of N-bromosuccinimide (313 mg, 1.76 mmol). The reaction was heated at 50° C. and stirred for 2.5 hours. The reaction was cooled, diluted with ethyl acetate and washed with water, saturated sodium bicarbonate, water, and brine. The organic layer was dried over MgSO4, filtered and concentrated. The material was purified using a Biotage 40M cartridge, gradient 5% ethyl acetate/hexane to 50% to yield the title compound (415 mg, 89.8% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13](O)=[O:14])[CH:5]=[CH:6][CH:7]=1.[NH:29]1[CH:36]=[CH:35][C:33]([NH2:34])=[N:32][C:30]1=[O:31]>>[O:31]=[C:30]1[N:32]=[C:33]([NH:34][C:13]([C:12]2[S:11][C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)=[N:9][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[O:14])[CH:35]=[CH:36][NH:29]1
Reactant: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(=O)O)s3)c2cc1OC
Reactant: Nc1cc[nH]c(=O)n1
Product: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(=O)Nc4cc[nH]c(=O)n4)s3)c2cc1OC
Yield: 11 %

Procedure:
In a similar manner as described for Example 53, 4-(3-Chloro-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (41 mg, 0.1 mmol) and cytosine (11.1 mg, 0.1 mmol, Aldrich) gave 4-(3-Chloro-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (2-oxo-1,2-dihydro-pyrimidin-4-yl)-amide (5.6 mg, 11.0%) as a white solid. MS m/z 509 (M+1).
Reaction SMILES: NC[CH:3]1[CH2:11][CH2:10][CH:9]2[N:5]([CH2:6][CH2:7][CH2:8]2)[C:4]1([CH3:13])[CH3:12].[CH:14]([N:17](CC)C(C)C)(C)C>C(O)C>[C:14]([CH:11]1[CH2:10][CH:9]2[N:5]([CH2:6][CH2:7][CH2:8]2)[C:4]([CH3:12])([CH3:13])[CH2:3]1)#[N:17]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC1(C)C(CN)CCC2CCCN21
Solvent: CCO
Product: CC1(C)CC(C#N)CC2CCCN21
Yield: 74.8 %

Procedure:
(±) Equatorial aminomethyl-2,2-dimethylazabicyclo[4.3.0]nonane (0.1 g, 0.0006 mole) was treated with mutilin 14-toluenesulfonyloxyacetate (0.25 g, 0.0005 mole), (K Biedl, J Antibiotics 29 (2), 133, 1976) and N,N-diisopropylethylamine (0.1 ml, 0.0006 mole) in ethanol (20 ml) and heated under reflux for 6 hours. The mixture was then concentrated in vacuo and the residue partitioned between saturated sodium hydrogen carbonate solution and dichloromethane. The organics were separated and dried (Na2SO4). Chromatography on silica gel eluting with chloroform/methanol/35% ammonia solution (90:9:1) gave the title compound 0.08 g, (31%); 1H NMR (CDCl3) 0.71 (3H, d, J 6.5 Hz) 0.90 (3H, d, J 6.5 Hz), 0.95 (3H, s), 1.25-2.55 (38H, m), 2.85-2.97 (1H, m), 3.19-3.39 (2H, m), 5.15 (1H, d, J 16.5 Hz), 5.31 (1H, d, J 11.1 Hz), 5.78 (1H, d, J 8.6 Hz), 6.50 (1H, dd, J 15.0 and 11.1 Hz). MS (+ve ion electrospray) m/z 543 (MH+, 100%).
Reaction SMILES: [C:1]([C:4]1[O:8][N:7]=[C:6]([O:9][CH2:10][C:11]([OH:13])=[O:12])[CH:5]=1)([OH:3])=[O:2].[C:14]1(C)C=CC(S(O)(=O)=O)=C[CH:15]=1>C(O)C>[C:1]([C:4]1[O:8][N:7]=[C:6]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=1)([OH:3])=[O:2]
Reactant: O=C(O)COc1cc(C(=O)O)on1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)COc1cc(C(=O)O)on1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(5-Carboxyisoxazol-3-yl)oxyacetic acid (4.0 mmol, Example 74) is dissolved in ethanol (50 mL), to which is added a catalytic amount of p-toluenesulfonic acid (100 mg). After stirring overnight at room temperature, the ethanol was removed and the residue was recrystallized from ethanol/water.
Reaction SMILES: C([NH:5][C:6]1[N:11]=[C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([F:24])=[C:19]([F:23])[C:20]=3[CH3:22])[C:15](=[O:25])[C:14]([C:26]([O:28]CC)=[O:27])=[CH:13]2)[C:9]([F:31])=[CH:8][C:7]=1[F:32])(C)(C)C>Cl>[NH2:5][C:6]1[N:11]=[C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([F:24])=[C:19]([F:23])[C:20]=3[CH3:22])[C:15](=[O:25])[C:14]([C:26]([OH:28])=[O:27])=[CH:13]2)[C:9]([F:31])=[CH:8][C:7]=1[F:32]
Reactant: CCOC(=O)c1cn(-c2nc(NC(C)(C)C)c(F)cc2F)c2c(C)c(F)c(F)cc2c1=O
Agent: Cl
Product: Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(-c3nc(N)c(F)cc3F)c12
Yield: 83.6 %

Procedure:
To 2.5 g of ethyl 1-[6-(t-butylamino)-3,5-difluoropyridine-2-yl]-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate was added 10 ml of 12N hydrochloric acid, and the mixture was heated overnight under reflux. The reaction solution was allowed to stand, and the solid precipitate was collected by filtration and washed with ethanol and then, with diethylether to obtain 1.7 g of the title compound as a pale yellow powder.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][C:5]1[C:9]2[C:10]([Cl:26])=[CH:11][C:12]([O:14][CH2:15][C:16]3[N:20]([CH3:21])[N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[CH:13][C:8]=2[S:7][C:6]=1[CH3:27].C1COCC1.[OH-].[Na+].Cl>CO>[Cl:26][C:10]1[C:9]2[C:5]([CH2:4][C:3]([OH:28])=[O:2])=[C:6]([CH3:27])[S:7][C:8]=2[CH:13]=[C:12]([O:14][CH2:15][C:16]2[N:20]([CH3:21])[N:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:17]=2)[CH:11]=1
Reactant: COC(=O)Cc1c(C)sc2cc(OCc3cc(C(F)(F)F)nn3C)cc(Cl)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1sc2cc(OCc3cc(C(F)(F)F)nn3C)cc(Cl)c2c1CC(=O)O
Temperature: 50 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To a mixture of methyl(4-chloro-2-methyl-6-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methoxy)-1-benzothiophen-3-yl)acetate (184.5 mg), THF (dry) (2.0 mL) and MeOH (2.0 mL) was added 1N NaOH (1.28 mL). The mixture was stirred at room temperature for 2 h and at 50° C. for 1 h. The mixture was neutralized with 1N HCl. The generated precipitate was collected by filtration to give a colorless solid. The solid was crystallized from EtOAc-hexane to give the title compound (161 mg).