Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:7]1[C:11]2[N:12]=[CH:13][C:14]3[C:15]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:16][C:17]4[N:18]([N:20]=[CH:21][N:22]=4)[C:19]=3[C:10]=2[CH:9]=[N:8]1)C1OC=CC=1.COCCOCCOC.[Se](=O)=O>>[C:24]1([O:23][C:15]2[C:14]3[CH:13]=[N:12][C:11]4[NH:7][N:8]=[CH:9][C:10]=4[C:19]=3[N:18]3[N:20]=[CH:21][N:22]=[C:17]3[N:16]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: c1ccc(Oc2nc3ncnn3c3c2cnc2c3cnn2Cc2ccco2)cc1
Agent: O=[Se]=O
Solvent: COCCOCCOC
Product: c1ccc(Oc2nc3ncnn3c3c2cnc2[nH]ncc23)cc1
Reaction time: 2 h

Procedure:
0.01 mol. of 8-furfuryl-5-phenyloxy-8H-pyrazolo-[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine is heated in 50 ml. of diethyleneglycol dimethyl ether containing 0.01 mol. of selenium dioxide at reflux temperature with stirring for 2 hours. The mixture is filtered hot and evaporated to dryness. 5-Phenyloxy-8H-pyrazolo-[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine remains.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[CH2:10]=O>O.[Pd]>[CH3:10][N:5]1[CH2:6][C@H:2]([OH:1])[CH2:3][C@H:4]1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: C=O
Agent: [Pd]
Solvent: O
Product: CN1C[C@H](O)C[C@H]1C(=O)O
Reaction time: 24 h
Yield: 98.3 %

Procedure:
To 40 g (305 mmol) of trans-4-hydroxy-L-proline in 80 ml of water was added 80 ml of 30% aqueous formaldehyde solution and 7.0 g of 5% palladium on carbon catalyst (50 % wet), and the mixture was hydrogenated at 50 psig using a Parr Shaker. After 24 hours, the catalyst was recovered by filtration over diatomaceous earth and the filtrate evaporated under reduced pressure to provide 43.5 g (98.3%) of title product; mp 140°-142° C. (decomposition); 1H-NMR (D2O): 4.65 (m, 1H), 4.20 (dd, 1H), 3.97 (dd, 1H), 3.2 (dm, 1H), 2.50 (m, 1H), 2.25 (m, 1H); [alpha]D =-54.8° (c=1.18, H2O).
Reaction SMILES: [F:1][C:2]1[C:9]([O:10]C)=[CH:8][CH:7]=[C:6]([I:12])[C:3]=1[C:4]#[N:5].B(Br)(Br)Br.O>ClCCl>[F:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([I:12])[C:3]=1[C:4]#[N:5]
Reactant: COc1ccc(I)c(C#N)c1F
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: N#Cc1c(I)ccc(O)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.9 %

Procedure:
A —78° C. solution of 2-fluoro-6-iodo-3-methoxybenzonitrile (148 mg, 0.53 mmol) in dichloromethane (5 mL) was treated dropwise with BBr3 (2.5 mL, 1M in dichloromethane, 2.5 mmol), warmed to room temperature, stirred for 18 hours, poured into water, and extracted with diethyl ether. The extract was dried (MgSO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 20% ethyl acetate/hexanes to provide 110 mg of the desired product. MS (ESI(−)) m/e 262 (M−H)−.
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[C:6]1[NH:16][C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]3[CH2:20][CH2:19][C:18]4([C:29](=[O:30])[C:28]5[C:23](=[C:24]([OH:40])[C:25]6[C:36](=[O:37])[CH:35]=[C:34](OC)[C:32](=[O:33])[C:26]=6[C:27]=5[OH:31])[C:21]4=[O:22])[C:11]=3[C:12]=2[OH:17])[CH:7]=1.[CH2:41]([NH2:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(#N)C.O>CN(C=O)C>[OH:31][C:27]1[C:26]2[C:32](=[O:33])[C:34]([NH:48][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:35][C:36](=[O:37])[C:25]=2[C:24]([OH:40])=[C:23]2[C:21](=[O:22])[C@:18]3([C:11]4[C:12]([OH:17])=[C:13]5[C:8]([CH:7]=[C:6](/[CH:5]=[CH:4]/[CH:3]=[CH:2]/[CH3:1])[NH:16][C:14]5=[O:15])=[CH:9][C:10]=4[CH2:20][CH2:19]3)[C:29](=[O:30])[C:28]=12
Reactant: C/C=C/C=C/c1cc2cc3c(c(O)c2c(=O)[nH]1)C1(CC3)C(=O)c2c(O)c3c(c(O)c2C1=O)C(=O)C(OC)=CC3=O
Reactant: NCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: C/C=C/C=C/c1cc2cc3c(c(O)c2c(=O)[nH]1)[C@@]1(CC3)C(=O)c2c(O)c3c(c(O)c2C1=O)C(=O)C(NCc1ccccc1)=CC3=O

Procedure:
Twenty (20) mg (37.1 μmol) fredericamycin are dissolved in 1 ml DMF under argon, then 4.76 mg (44.50 μmol) benzylamine are added at room temperature. According to HPLC (RP18, acetonitrile/water), a homogenous new product has formed after 3 h. The reaction mixture is concentrated at high vacuum until dry.
Reaction SMILES: C(OC([N:8]([CH2:19][CH2:20][CH2:21][P:22](=[O:33])([O:28]CCCC)[O:23]CCCC)[O:9]CC1C=CC(OC)=CC=1)=O)C(C)C.Cl>C(O)(=O)C>[OH:9][NH:8][CH2:19][CH2:20][CH2:21][P:22](=[O:23])([OH:33])[OH:28]
Reactant: CCCCOP(=O)(CCCN(OCc1ccc(OC)cc1)C(=O)OCC(C)C)OCCCC
Agent: Cl
Solvent: CC(=O)O
Product: O=P(O)(O)CCCNO
Reaction time: 21 h
Yield: 53.1 %

Procedure:
A mixture of dibutyl 3-[N-isobutoxycarbonyl-N-(p-methoxybenzyloxy)amino]propylphosphonate (6.04 g), conc. hydrochloric acid (60 ml) and acetic acid (60 ml) was refluxed with stirring for 21 hours. The resultant mixture was concentrated under reduced pressure, and to the residue was added water. The mixture was concentrated under reduced pressure to give a residue, which was washed with acetonitrile and then dissolved in water (10 ml). To the solution were added pyridine (800 ml) and ethanol (4 ml), and then the mixture was allowed to stand overnight at 4° C. to give 3-(N-hydroxyamino)propylphosphonic acid (1.02 g) in the form of crystals. MP: 160°~166° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:11])C=O)=[CH:4][CH:3]=1.[CH:12](OCC)(OCC)[O:13][CH2:14][CH3:15].Cl[CH2:23]Cl>C(OCC)C>[CH2:14]([O:13][CH:12]1[C:4]2[C:5](=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[CH:8]=[C:11]1[CH3:23])[CH3:15]
Reactant: ClCCl
Reactant: CCOC(OCC)OCC
Reactant: C=C(C=O)c1ccc(C)cc1
Solvent: CCOCC
Product: CCOC1C(C)=Cc2ccc(C)cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 24 %

Procedure:
Anhydrous FeCl3 (2.0 g, 12.3 mmol.) was added to a solution of (2E)-2-methyl-3-(4-methylphenyl-2-propenal (5.0 g, 31.3 mmol.) and triethyl orthoformate (5.1 g, 34.5 mmol.) in dichloromethane (35 ml). The dark red solution was stirred at room temperature for 1 day, then diluted with 100 ml of diethyl ether and washed with water (3×75 ml). The organic phase was dried (MgSO4), filtered and concentrated. Kugelrohr distillation (54° C., 20 mTorr) yielded 1.4 g (7.4 mmol., 24% yield) of the title compound.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]#[N:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21][CH2:22]Br.[OH-].[Na+].O>CS(C)=O>[C:15]([C:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1)([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:22][Br:21])#[N:16]
Reactant: CCCCC(C#N)c1cccc(Oc2ccccc2)c1
Reactant: BrCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCCC(C#N)(CBr)c1cccc(Oc2ccccc2)c1
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To a solution of 10 g (0.038 mole) of 2-(3-phenoxyphenyl)hexanenitrile, 6.6 g (0.038 mole) of dibromomethane in 50 ml of dimethyl sulfoxide is added 3.2 g (0.04 mole) of 50% sodium hydroxide solution dropwise. The reaction mixture is stirred at 60° for one hour, poured into water and extracted with ether. The combined ether extracts are washed with water and dried over MgSO4. Solvent is evaporated to give 12 g of product.
Reaction SMILES: O.[NH2:2][NH2:3].C(OCC)C.[CH3:9][C:10](=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:11]=O>O>[CH3:9][CH:10]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:3][N:2]=[CH:11]1
Reactant: NN
Reactant: CC(C=O)=Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: CC1C=NNC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.22 ml (1 equiv.) hydrazine hydrate was added to 100 mL diethylether. The emulsion was cooled with an ice bath. 15.0 mL 2-Methyl-3-phenyl-propenal was added dropwise, and the mixture was stirred overnight at room temperature. H2O was added, the organic layer was separated and the aqueous layer was extracted with diethylether. The combined organic layers were dried over Na2SO4, filtrated and concentrated in vacuo. Vacuum destillation yielded 5.9 g of desired product (mixture of diastereomeric pairs) as a clear fluid (76-82° C., 0.2-0.3 mbar). 1H NMR (400 MHz, CDCl3) of first diastereomeric pair: δ 0.71 (d, J=7 Hz), 3H), 3.20-3.31 (m, 1H), 4.77 (d, J=10 Hz, 1H), 6.73 (br s, 1H), 7.23-7.42 (m, 5H), 8.55-8.60 (m, 2H). 1H NMR (400 MHz, CDCl3) of second diastereomeric pair: δ 1.24 (d, J=7 Hz), 3H), 2.90-3.11 (m, 1H), 4.22 (d, J=11 Hz, 1H), 6.71 (br s, 1H), 7.23-7.42 (m, 5H), 8.55-8.60 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](O)=[O:8])[C:4]([CH3:10])=[N:3]1.C(Cl)(=O)C(Cl)=O.[NH2:17][C:18]1[CH:19]=[C:20]([CH:37]=[CH:38][C:39]=1[F:40])[O:21][C:22]1[CH:23]=[CH:24][C:25]2[N:26]([CH:28]=[C:29]([NH:31][C:32]([CH:34]3[CH2:36][CH2:35]3)=[O:33])[N:30]=2)[N:27]=1>CN(C)C=O.O1CCCC1.C(OCC)(=O)C>[CH:34]1([C:32]([NH:31][C:29]2[N:30]=[C:25]3[CH:24]=[CH:23][C:22]([O:21][C:20]4[CH:37]=[CH:38][C:39]([F:40])=[C:18]([NH:17][C:7]([C:5]5[C:4]([CH3:10])=[N:3][N:2]([CH3:1])[CH:6]=5)=[O:8])[CH:19]=4)=[N:27][N:26]3[CH:28]=2)=[O:33])[CH2:35][CH2:36]1
Reactant: Cc1nn(C)cc1C(=O)O
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1nn(C)cc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Yield: 39.2 %

Procedure:
To a solution of 1,3-dimethyl-1H-pyrazole-4-carboxylic acid (140 mg, 1.0 mmol) and N,N-dimethylformamide (2 drops) in tetrahydrofuran (10 mL) was added oxalyl chloride (0.171 mL, 2.0 mmol) with stirring under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in N-methylpyrrolidone (5 mL) with stirring under ice-cooling, N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (164 mg, 0.50 mmol) was added, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with ethyl acetate (80 mL), and washed with 1N aqueous sodium hydroxide solution (10 mL) and water (10 mL×3). The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→70/30) and recrystallized from ethyl acetate to give the title compound (88 mg, yield 39%) as a white solid. melting point 205° C.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([OH:10])[CH2:6][N:5]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:12])(O)=[O:2].C(N(CC)CC)C.ClC(OCC)=O.[NH3:37].[S:38](Cl)([CH3:41])(=[O:40])=[O:39]>C1COCC1>[C:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([O:10][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:6][N:5]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:12])(=[O:2])[NH2:37]
Reactant: CS(=O)(=O)Cl
Reactant: N
Reactant: O=C(O)[C@@H]1CC[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]1CC[C@@H](C(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: -40 °C
Reaction time: 0.83 h
Yield: 71 %

Procedure:
To a solution of 490 mg (1.51 mmol) of (2S,5R)-2-carboxy-5-hydroxy-1-p-nitrobenzyloxycarbonylpiperidine, which was prepared from the compound of Example 8-2) by a conventional method for the deprotection, in 8 ml of THF was dropwise added 0.23 ml (1.65 mmol) of triethylamine followed by 0.16 ml (1.67 mmol) of ethyl chloroformate at -30° C., and the mixture was stirred for 50 minutes at the same temperature. The mixture was cooled to -40° C., and 1.5 ml of concentrated aqueous ammonia was dropwise added. The reaction mixture was gradually warmed to room temperature and then stirred for 1 hour. The solvent was removed, and the residue was purified by silica gel column chromatography (Wakogel® C-300, elution with methanol - chloroform system). To a solution of the resulting compound in 10 ml of THF was dropwise added 0.47 ml (3.37 mmol) of triethylamine followed by 0.26 ml (3.36 mmol) of mesyl chloride, and the mixture was stirred for 2 hours at room temperature. The solvent was removed, and the residue was purified by silica gel column chromatography (Wakogel® C-300, elution with methanol - chloroform system) to give 430 mg (yield: 71%) of the title compound.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][N:8]=1.[Li][CH2:15]CCC.CI.[NH4+].[Cl-]>CCOCC>[Cl:13][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([C:6]2[CH:5]=[CH:4][S:3][C:2]=2[CH3:15])[CH:12]=1
Reactant: Clc1ccnc(-c2ccsc2Br)c1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: CCOCC
Product: Cc1sccc1-c1cc(Cl)ccn1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(2-bromo-thiophen-3-yl)-4-chloro-pyridine (80 mg, 0.3 mmol) in Et2O (3 mL) at −78° C. was added n-BuLi (1.6 M in hexanes, 0.2 mL). After 10 min, MeI (70 mg, 0.5 mmol) was added. The resulting mixture was maintained at −78° C. for 2 h, then was warmed to room temperature and stirred for 3 h. The reaction mixture was treated with 2 M aqueous NH4Cl and extracted with EtOAc. The organic layer was dried and concentrated to yield a residue. The residue was purified by preparative TLC (hexanes/EtOAc) to yield 4-chloro-2-(2-methyl-thiophen-3-yl)-pyridine as a solid.
Reaction SMILES: [F:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[N:4][CH:5]=[C:6]([CH2:8][NH:9][C:10](=[O:23])[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:13][N:12]=2)[CH:7]=1.CCN(C(C)C)C(C)C.Cl[C:44]([O:46][CH3:47])=[O:45]>C1COCC1>[F:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=2)=[N:4][CH:5]=[C:6]([CH2:8][NH:9][C:10]([C:11]2[N:12]=[CH:13][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:44]([O:46][CH3:47])=[O:45])[CH2:19][CH2:18]3)=[CH:15][CH:16]=2)=[O:23])[CH:7]=1
Reactant: O=C(NCc1cnc(-c2ccnc(C(F)(F)F)c2)c(F)c1)c1ccc(N2CCNCC2)cn1
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CCN(c2ccc(C(=O)NCc3cnc(-c4ccnc(C(F)(F)F)c4)c(F)c3)nc2)CC1
Reaction time: 2 h

Procedure:
To a solution of N-((3-fluoro-2′-(trifluoromethyl)-2,4′-bipyridin-5-yl)methyl)-5-(piperazin-1-yl)picolinamide 49-6 (64 mg, 0.14 mmol) and DIEA (0.07 mL, 0.42 mmol) in THF (1 mL) was added methyl chloroformate (13 uL, 0.17 mmol) dropwise at room temperature. The mixture was stirred for 2 hours. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give methyl 4-(6-((3-fluoro-2′-(trifluoromethyl)-2,4′-bipyridin-5-yl)methylcarbamoyl)pyridin-3-yl)piperazine-1-carboxylate 93 as a white powder. MS m/z 519.20 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 9.28 (t, 1H, J=6.4 Hz), 8.92 (d, 1H, J=5.2 Hz), 8.62 (m, 1H), 8.32 (m, 2H), 8.20 (d, 1H, J=5.2 Hz), 7.88-7.82 (m, 2H), 7.43 (dd, 1H, J1=7.0 Hz, J2=3.2 Hz), 4.59 (d, 2H, J=6.4 Hz), 3.73 (s, 3H), 3.54-3.51 (m, 4H), 3.37-3.35 (m, 4H).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[S:23][CH:24]=[CH:25][C:26]=4[CH3:27])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:28](OCC)=[O:29].[O-]CC.[Na+].Cl>C(O)C>[OH:29][CH:28]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[S:23][CH:24]=[CH:25][C:26]=4[CH3:27])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCOC=O
Reactant: Cc1ccsc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ccsc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Temperature: 78 °C
Yield: 67.1 %

Procedure:
3-Methyl-thiophene-2-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.925 g, 2.4573 mmol) and ethyl formate (0.59 mL, 7.33 mmol) were dissolved in anhydrous ethanol (25 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (4.583 mL, 12.28 mmol). This reaction mixture was heated at 78° C. for 0.5 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a tan precipitate. The suspension was filtered and the solids were washed with 0° C. EtOH to afford the pure 3-Methyl-thiophene-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.6659 g, 1.65 mmol, 67%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[C:15](\[O:20][CH3:21])/[C:16]([O:18][CH3:19])=[O:17])=[CH:10][C:9]=2[O:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:5]=[CH:6][CH:7]=1.[CH2:27]([N:34]=[C:35]=[O:36])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>CCOCC>[CH2:23]([O:22][C:9]1[CH:10]=[C:11](/[CH:14]=[C:15](\[O:20][CH3:21])/[C:16]([O:18][CH3:19])=[O:17])[CH:12]=[CH:13][C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:35]([NH:34][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:36])[CH:3]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCN=C=O
Reactant: CCCCOc1cc(/C=C(\OC)C(=O)OC)ccc1-c1cccc(N)c1
Solvent: CCOCC
Product: CCCCCCCNC(=O)Nc1cccc(-c2ccc(/C=C(\OC)C(=O)OC)cc2OCCCC)c1
Yield: 78.9 %

Procedure:
376 mg (1.1 mmol) of methyl (Z)-3-(3′-amino-2-butoxybiphenyl-4-yl)-2-methoxyacrylate and 0.3 mL (2.2 mmol) of heptyl isocyanate are heated at 100° C. by microwave in an Emrys Optimizer machine for 20 minutes. The residue obtained is taken up in ether and then filtered by suction. 431 mg (79%) of methyl (Z)-3-[2-butoxy-3′-(3-heptylureido)biphenyl-4-yl]-2-methoxyacrylate are obtained in the form of a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](Cl)[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11].[H-].[Na+].[CH2:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])c(OC)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 5-chloro-2-nitrophenyl methyl ether (5 g, 26.596 mmol) in dry DMF (150 mL) was cooled to 0° C. by ice water and NaH (3.51 g, 87.750 mmol, 60% purity) was added portionwise, and then the reaction was warmed to ambient temperature and stirred for 1.5 hours. The reaction was cooled to 0° C. and CH2(COOEt)2 (14.04 g, 87.768 mmol) was added. The result mixture was warmed to ambient temperature and heated to 80° C. for 13 hours. The reaction was cooled to ambient temperature and poured into ice water and added 2N HCl to adjust pH to 3. Extracted with EtOAc and the organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified via column chromatograph to afford diethyl (3-methoxy-4-nitrophenyl)propanedioate. 1H-NMR (400 MHz, CDCl3) δ ppm 7.86 (d, J=8.3 Hz, 1H), 7.25 (s, 1H), 7.07 (d, J=8.3 Hz, 1H), 4.67 (s, 1H), 4.23˜4.29 (m, 4H), 4.00 (s, 3H), 1.31 (t, J=7.0 Hz, 6H).
Reaction SMILES: [C:1](=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[C:9]([C:21]#[C:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][CH:35]([CH3:38])[CH2:34][CH2:33]3)=[CH:25][CH:24]=2)=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:13]=1.COB(O)O>O1CCOCC1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:13]=[C:8]([CH3:1])[C:9]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH:35]([CH3:38])[CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[N:10][CH:11]=2)=[CH:15][CH:16]=1
Reactant: CC1CCN(CCOc2ccc(C#Cc3ncc(-c4ccc(Cl)cc4)cc3Br)cc2)CC1
Reactant: O=C([O-])[O-]
Agent: COB(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc(Cl)cc2)cnc1C#Cc1ccc(OCCN2CCC(C)CC2)cc1

Procedure:
2.5 n-L of 2M aqueous sodium carbonate solution and 15 mg (0.013 mmol) of tetrakis(triphenylphosphane)palladium were added under argon to a suspension of 130 mg (0.255 mmol) of 3-bromo-5-(4-chlorophenyl)-2-{4-[2-(4-methylpiperidin-1-yl)ethoxy]phenylethynyl}pyridine and 18.9 mg (0.306 mmol) of methylboric acid in 5 mL of 1,4-dioxane and the mixture was refluxed for 5 hours. A further 18.9 mg (0.306 mmol) of methylboric acid was added and again the mixture was refluxed for 2 hours. The reaction mixture was exhaustively extracted with EtOAc, the combined organic phases were washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, and evaporated down in vacuo. The residue was purified by HPLC-MS (Symmetry C18, gradient 0.15% formic acid in water/acetonitrile 10/90→50/50 v/v) and the product fractions were lyophilized. Product fraction 1: Yield: 12 mg (11% of theoretical); C28H29ClN2O (M=444.995); calc.: molpeak (M+H)+: 445/447 (Cl); found: molpeak (M+H)+: 445/447 (Cl); HPLC-MS: 4.00 minutes (method E).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:11]3[CH2:12][S:13][CH2:14][C:10]3=[C:9]([C:15]([OH:17])=O)[CH:8]=2)[CH:2]=1.CN(C)C=O.[Cl:23]CCCl>S(Cl)(Cl)=O.C1CCCCC1>[ClH:23].[Cl:23][C:15]([C:9]1[CH:8]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:11]2[C:10]=1[CH2:14][S:13][CH2:12]2)=[O:17]
Reactant: ClCCCl
Reactant: O=C(O)c1cc(-c2cccnc2)n2c1CSC2
Solvent: CN(C)C=O
Solvent: C1CCCCC1
Solvent: O=S(Cl)Cl
Product: Cl
Product: O=C(Cl)c1cc(-c2cccnc2)n2c1CSC2
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A suspension of 5-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxylic acid (8.8 g) in a mixture of thionyl chloride (6.25 cc), dimethylformamide (0.05 cc) and 1,2dichloroethane (100 cc) is heated under reflux with stirring for 2 hours and 30 minutes. The reaction mixture is cooled to a temperature of about 20° C. and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 60° C. The residue obtained is suspended in cyclohexane (150 cc) and the solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 60° C. The same procedure is repeated twice. 7- Chloroformyl-5-(3-pyridyl)-pyrrolo[1,2-c]thiazole hydrochloride (10 g) is thus obtained in the form of cream crystals melting at 220° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:5]=[C:6]([N+:14]([O-])=O)[C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[H][H]>[Pd]>[NH2:14][C:6]1[CH:5]=[C:4]([C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CCOC(=O)C(=O)c1cc(Cl)c(C2CCCCC2)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CO
Product: CCOC(=O)C(=O)c1cc(N)c(C2CCCCC2)c(Cl)c1

Procedure:
A mixture of 17.6 g. (0.05 moles) of ethyl 3-chloro-5-nitro-4-cyclohexylphenylglyoxylate in 100 ml. of methanol containing 0.05 moles of citric acid and 1.5 g. of 5% palladium-on-carbon is shaken with hydrogen at 3 atm. pressure and 27°C until 3 moles of hydrogen are absorbed. The mixture is filtered, washed with methanol and the filtrate concentrated in vacuo to obtain ethyl 3-amino-5-chloro-4-cyclohexylphenylglyoxylate isolated as the citrate salt.