Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[N:5]([N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:16]=2)[C:6](=O)[C:7]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:6]1[N:5]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:16]=[C:4]2[N:3]=[C:2]([CH3:1])[C:7]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)Cc1c(C)[nH]c2cc(-c3ccccc3)nn2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)Cc1c(C)nc2cc(-c3ccccc3)nn2c1Cl
Temperature: 0 °C
Yield: 86.9 %

Procedure:
To methyl 2-(5-methyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)acetate (3 g, 10.09 mmol) was added POCl3 (25 mL, 268 mmol). The reaction mixture was heated at reflux for 1 h. After cooling, the reaction mixture was added drop-wise to ice-water. A brown solid precipitated. The solid was filtered and washed with water, then dissolved in ethyl acetate. The organic solution was washed with saturated NaHCO3 and dried over sodium sulfate. The solvent was evaporated to give the title compound (2.77 g, 84%). 1H-NMR (400 MHz, DMSO-d6) δ 2.58 (3H, s), 3.71 (3 H, s), 4.04 (2 H, s), 7.29 (1 H, s), 7.43-7.58 (3 H, m), 8.07 (2 H, d, J=7.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1.Br[CH2:15]CO.Cl>C1COCC1>[Cl:12][C:7]1[CH:6]=[C:5]([CH:4]2[CH2:15][CH2:1][O:2][C:3]2=[O:13])[CH:10]=[CH:9][C:8]=1[Cl:11]
Reactant: COC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: OCCBr
Agent: Cl
Solvent: C1CCOC1
Product: O=C1OCCC1c1ccc(Cl)c(Cl)c1
Temperature: 45 °C
Reaction time: 2.5 h

Procedure:
Heat [(CH3)3Si]2NLi (230 ml, 1.0M in THF) under N2 to 45° C. and add 3,4 dichlorophenyl acetic acid methyl ester (40 g, 0.183 moles) dissolved in 60 ml of dry THF dropwise over 2 h. Stir the solution at 45° C. for another 2.5 h. Cool the solution to room temperature, add a dry THF solution (30 ml.) of THP-protected Br(CH2)2OH dropwise over 1 h., and stir the solution for 24 h. Cool the solution in an ice bath and quench the reaction by adding, dropwise, 250 ml. of 1.0M aqueous HCl. Extract the solution with Et2 O, wash the organic layer twice with 1.0M aqueous HCl, then with water, and dry over anhydrous Na2SO4. Remove the solvent, dissolve the residue in CH3OH and add 0.5 g of pTSA. Stir the solution at room temperature overnight, remove the solvent, add CH3OH (500 ml) and stir for 6 h. Remove the solvent again, add more CH3OH (500 ml.), stir overnight and remove the solvent. Dissolve the resulting oil in CH2Cl2 (1200 ml.), wash twice with saturated aqueous NaHCO3, then water, and dry over anhydrous Na2SO4. Remove the solvent in vacuo. Purify the reaction mixture by flash chromatography (SiO2) using EtOAc: hexanes (3:7) as eluent. Yield: 22 g. Cl-MS: 231 (100%), 233 (65%).
Reaction SMILES: [C:1]([NH:6][C:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:8]=1)(=O)[CH2:2][CH2:3][CH3:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:1]([NH:6][C:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=2)[N:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)NC1=NN(c2cccc(C(F)(F)F)c2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCCCNC1=NN(c2cccc(C(F)(F)F)c2)CC1

Procedure:
According to the method of Example 1, 3-butyramido-1-(3-trifluoromethylphenyl)-2-pyrazoline was reduced with lithium aluminium hydride to produce 3-butylamino-1-(3-trifluoromethylphenyl)-2-pyrazoline which was a gum (yield 2.4 g) and was recrystallized as the hydrochloride m.p. 173.4° (yield 1.65 g).
Reaction SMILES: C([N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]([CH2:21][CH3:22])[C:12](=[O:23])[C:11]=2[N:10]=[CH:9]1)C1C=CC=CC=1>C(O)(=O)C.[C].[Pd]>[CH2:21]([N:13]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[C:20]2[NH:8][CH:9]=[N:10][C:11]=2[C:12]1=[O:23])[CH3:22]
Reactant: CCn1c(=O)c2ncn(Cc3ccccc3)c2c2ccccc21
Agent: [Pd]
Solvent: CC(=O)O
Product: CCn1c(=O)c2nc[nH]c2c2ccccc21
Temperature: 70 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
3.0 g (0.0099 mol) of Compound e obtained in Reference Example 4 was dissolved in 110 ml of acetic acid. 0.89 g of 10% palladium carbon was added to the solution. Under hydrogen stream, the solution was stirred 3 hours at 70° C. After filtration, the filtrate was concentrated under reduced pressure. Anhydrous sodium carbonate was added to the solution for neutralization, and a precipitate was collected by filtration and recrystallized from isopropanol-water, to afford 2.0 g (yield: 93%) of Compound h.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[O:9]([CH2:16][C:17](O)=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>Cl>[O:9]([CH2:16][C:17]1[NH:8][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[N:7]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)COc1ccccc1
Reactant: Nc1ccccc1N
Agent: Cl
Product: c1ccc(OCc2nc3ccccc3[nH]2)cc1
Temperature: 130 °C
Reaction time: 18 h
Yield: 89.6 %

Procedure:
A 100 mL flask fitted with a stir-bar and condenser was charged with 1,2-phenylenediamine (9.94 g, 92.1 mmol), phenoxyacetic acid (14.0 g, 92.1 mmol), and 4M HCl (140 mL). The suspension was heated in a 130° C. bath forming a green solution. After 18 hr, the reaction had gone to completion as monitored by HPLC. The mixture was cooled in an ice bath forming a solid. The solid was filtered, pressed with rubber dam, and rinsed with H2O (2×15 mL). The residue was partitioned with EtOAc (300 mL) and saturated NaHCO3 (125 mL). The organic phase was washed with brine (100 mL), filtered through phase separation paper, and concentrated in vacuo to give 18.5 g of 61 as an off-white solid (90%). 1H NMR (300 MHz, CDCl3): δ 10.08 (bs, 1H), 7.82-7.40 (bm, 2H), 7.35-7.26 (m, 4H), 7.08-6.95 (m, 3H), 5.40 (s, 2H) ppm. HPLC analysis (15:10:75 H2O:A1:MeOH) showed a purity of greater than 99% with a retention time of 4.2 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8](Br)=[CH:9][CH:10]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:19][C:20]([CH3:24])([CH3:23])[C:21]#[CH:22]>CN(C=O)C.[Cu](I)I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([C:22]#[C:21][C:20]([CH3:24])([CH3:23])[CH3:19])=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: C#CC(C)(C)C
Reactant: CCOC(=O)c1ccc(Br)s1
Agent: I[Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#CC(C)(C)C)s1
Yield: 97.3 %

Procedure:
A mixture of 5-bromo-thiophene-2-carboxylic acid ethyl ester (7 g, 30 mmol), copper iodide (1.2 g, 6 mmol), triethylamine (20 mL) in DMF (100 mL) was degassed in a 350 mL pressure bottle. Then tris(dibenzylideneacetone)dipalladium(0) (2.1 g, 3 mmol) and 3,3-dimethyl-but-1-yne (18.3 mL, 150 mmol) were added and heated at 80 degree for 3 hours. The reaction mixture was filtered on celite and washed with ethyl acetate. The solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and washed with water. After drying and concentration, the crude residue was purified by flash chromatography to yield 6.9 g (95%) of 5-(3,3-Dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid ethyl ester as a yellow oil.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][S:13][S:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].CCN=C=NCCCN(C)C>CC#N.CCOC(C)=O>[C:1]([NH:10][CH2:11][CH2:12][S:13][S:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cccnc1
Reactant: CC(C)(C)OC(=O)NCCSSCCN
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCSSCCNC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.9 %

Procedure:
Separately, nicotinic acid (246 mg, 2.0 mmol) was taken up in CH3CN (10 mL) along with tert-butyl 2-(2-(2-aminoethyl)disulfanyl)ethylcarbamate (503 mg, 2.0 mmol), EDCI (422 mg, 2.2 mmol). The resulting reaction mixture was stirred at room temperature for 4 h and then diluted with EtOAc. The organic layer was washed with dilute aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (CH2Cl2) afforded tert-butyl 2-(2-(2-(nicotinamido)ethyl)disulfanyl)ethylcarbamate (400 mg, 56%).
Reaction SMILES: C(OC([C:6]1[S:7][CH:8]=[C:9]2[C:14]=1[NH:13][C:12](=[O:15])[CH:11]=[C:10]2Cl)=O)C.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[CH2:17]([O:21][C:22]([C:11]1[C:12](=[O:15])[NH:13][C:14]2[C:9]([C:10]=1[N:27]1[CH2:28][CH2:29][N:24]([C:22]([O:21][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:23])[CH2:25][CH2:26]1)=[CH:8][S:7][CH:6]=2)=[O:23])[CH3:18]
Reactant: CCOC(=O)c1scc2c(Cl)cc(=O)[nH]c12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CCOC(=O)c1c(N2CCN(C(=O)OC(C)(C)C)CC2)c2cscc2[nH]c1=O

Procedure:
In another method, intermediate 7-chloro-5-oxo-4,5-dihydro-2-thia-4-aza-indene-3-carboxylic acid ethyl ester, depicted by formula (25), was reacted with tert-butyl-1-piperazine carboxylate to yield 7-(4-tert-butoxycarbonyl-piperazin-1-yl)-5-oxo-4,5-dihydro-2-thia-4-aza-indene-6-carboxylic acid ethyl ester, depicted by formula (28). This intermediate was either reacted with an appropriate halide (R1—X) or boronic acid (R1—B(OH)2) to yield an intermediate of structure (29), which was deprotected and reacted with an appropriate acid chloride (R3—COCl) or acid (R3—COOH) to yield target compounds of structure (II), with R2 as ethyl carboxylate, and R1 and R3 as defined above, as shown in Scheme 14.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([NH:9][CH2:10][C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][C:16]([Cl:22])=[CH:17][CH:18]=3)[N:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:12]=2)=[O:8])=[CH:5][N:6]=1.[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>CN1C(=O)CCC1>[Cl:22][C:16]1[CH:15]=[C:14]2[C:19]([C:20](=[O:21])[C:11]([CH2:10][NH:9][C:7]([C:4]3[S:3][C:2]([N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[N:6][CH:5]=3)=[O:8])=[CH:12][N:13]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1cnc(Br)s1
Reactant: C1CCNCC1
Solvent: CN1CCCC1=O
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1cnc(N2CCCCC2)s1
Temperature: 120 °C

Procedure:
A mixture of 2-bromo-N-((7-chloro-4-oxo-1-phenyl-1,4-dihydroquinolin-3-yl)methyl)-thiazole-5-carboxamide (intermediate F) (30 mg, 0.063 mmol) and piperidine (10.8 mg, 0.126 mmol) in NMP was heated to 120° C. in a sealed microwave tube. After heating for 2 hr., the mixture was allowed to cool to room temperature. The crude product was purified using preparative reverse-phase HPLC, providing 2-piperidin-1-yl-thiazole-5-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide. MS calcd. for C25H23ClN4O2S [(M+H)+] 479.1, obsd. 478.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]1[C:7]([C:8]([C:17]([O:19]C)=[O:18])=[CH:9][CH:10]=[CH:11]1)=[N:6]2>CO.O>[F:22][C:2]([F:1])([F:21])[C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]1[C:7]([C:8]([C:17]([OH:19])=[O:18])=[CH:9][CH:10]=[CH:11]1)=[N:6]2
Reactant: COC(=O)c1cccc2cc3ccc(C(F)(F)F)cc3nc12
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc2cc3ccc(C(F)(F)F)cc3nc12
Yield: 81 %

Procedure:
Cyclization of this as above, followed by immediate hydrolysis of the crude methyl 6-trifluoromethylacridine-4-carboxylate, gave 6-trifluoromethylacridine-4-carboxylic acid (81%), mp (MeOH/H2O) 244-246° C. 1H NMR [(CD3)2SO] δ 7.93 (t, J=7.9 Hz, 1 H, H-3), 7.98 (dd, J=8.9, 1.5 Hz, 1 H, ArH), 8.56 (d, J=8.8 Hz, 1 H, ArH), 8.60 (d, J=8.5 Hz, 1 H, ArH), 8.79 (dd, J=7.0, 1.1 Hz, 1 H, ArH), 8.86 (s, 1 H, H-5), 9.66 (s, 1 H, H-9).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[NH:12]1[CH2:17][CH2:16][C:15](O)(O)[CH2:14][CH2:13]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:15]1[CH2:16][CH2:17][NH:12][CH2:13][CH:14]=1
Reactant: OC1(O)CCNCC1
Reactant: COc1ccc2[nH]ccc2c1
Product: COc1ccc2[nH]cc(C3=CCNCC3)c2c1

Procedure:
The experimental protocol used is described in the literature (Eur. J. Med. Chem. (1987) 22, 33-43), starting from 5-methoxy-1H-indole and 4,4-piperidinediol.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])=[O:11])=[C:8]([O:23][CH3:24])[CH:7]=1.N1C=CC=CC=1>C1C=CC=CC=1>[F:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([Cl:3])=[O:15])=[O:11])=[C:8]([O:23][CH3:24])[CH:7]=1
Reactant: COc1cc(F)ccc1C(=O)c1ccccc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COc1cc(F)ccc1C(=O)c1ccccc1C(=O)Cl

Procedure:
Thionyl chloride (1.5 ml) was added to a solution of 2-(4-fluoro-2-methoxybenzoyl)benzoic acid (mp 119°-120° C.) (3.66 g) and pyridine (0.03 ml) in benzene (50 ml), followed by refluxing for an hour. The solvent was distilled off to give 2-(4-fluoro-2-methoxybenzoyl)benzoyl chloride (IRνmaxNujol : 1795 cm-1). A solution of this product in methylene chloride (40 ml) was added to a solution of ethyl 4-isopropylaminocrotonate (Reference Example I) (3.6 g) and triethylamine (3.0 ml) in methylene chloride (40 ml), followed by stirring at room temperature for 16 hours. After removing the solvent, ethyl acetate was added to the residue. The mixture was washed with water, dil. hydrochloric acid, water, sodium hydrogen carbonate solution and water in turn. The ethyl acetate layer was dried over anhydrous sodium sulfate and distilled to give the title compound (5.50 g) as pale brown oily substance.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[F:16])[N:12]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[CH:11]=[CH:10]2.[CH2:24]([NH:26][CH2:27][CH2:28][OH:29])[CH3:25]>>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([N:12]2[C:13]3[C:9](=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:26]([CH2:24][CH3:25])[CH2:27][CH2:28][OH:29])=[C:15]([F:16])[CH:14]=3)[CH:10]=[CH:11]2)=[CH:18][CH:19]=1
Reactant: CCNCCO
Reactant: Fc1cc2c(ccn2-c2ccc(Cl)cc2)cc1OCCCCBr
Product: CCN(CCO)CCCCOc1cc2ccn(-c3ccc(Cl)cc3)c2cc1F

Procedure:
In analogy to example 23.7, 5-(4-Bromo-butoxy)-1-(4-chloro-phenyl)-6-fluoro-1H-indole and 2-(ethylamino)ethanol were converted to yield 2-({4-[1-(4-Chloro-phenyl)-6-fluoro-1H-indol-5-yloxy]-butyl}-ethyl-amino)-ethanol as a colorless oil, MS: 405 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[CH3:15][C:16]1[N:17]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:34])([F:33])[CH:30]([F:32])[F:31])=[CH:24][CH:23]=2)[C:18](=[O:21])[NH:19][N:20]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:19]1[C:18](=[O:21])[N:17]([C:22]2[CH:23]=[CH:24][C:25]([O:28][C:29]([F:33])([F:34])[CH:30]([F:31])[F:32])=[CH:26][CH:27]=2)[C:16]([CH3:15])=[N:20]1)[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: Cc1n[nH]c(=O)n1-c1ccc(OC(F)(F)C(F)F)cc1
Product: Cc1nn([C@H](C)[C@@]2(c3ccc(F)cc3F)CO2)c(=O)n1-c1ccc(OC(F)(F)C(F)F)cc1
Yield: 48.8 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.50 g of (1S)-1-[(2R)-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 0.58 g of 5-methyl-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-3(2H,4H)-1,2,4-triazolone, 0.46 g of 2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-5-methyl-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-3(2H,4H)-1,2,4-triazolone was obtained as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[C:5]([N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:20]([C:22]3[NH:23][C:24]([CH3:29])=[C:25]([Cl:28])[C:26]=3[Cl:27])=[O:21])[CH2:15][CH2:14]2)[S:6][C:7]=1[C:8]([O:10]CC)=[O:9].[CH2:30]([N:32]=[C:33]=[O:34])[CH3:31]>>[Cl:27][C:26]1[C:25]([Cl:28])=[C:24]([CH3:29])[NH:23][C:22]=1[C:20]([NH:19][CH:16]1[CH2:15][CH2:14][N:13]([C:5]2[S:6][C:7]([C:8]([OH:10])=[O:9])=[C:3]([CH2:2][NH:1][C:33]([NH:32][CH2:30][CH3:31])=[O:34])[N:4]=2)[CH2:18][CH2:17]1)=[O:21]
Reactant: CCN=C=O
Reactant: CCOC(=O)c1sc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc1CN
Product: CCNC(=O)NCc1nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)sc1C(=O)O

Procedure:
The title compound was prepared in a manner analogous to Example 250 from ethyl 4-(aminomethyl)-2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-thiazole-5-carboxylate (Example 246) and ethyl isocyanate.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH3:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.[CH3:16][O:17][C:18]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:19]=1[CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>ClCCCl>[CH3:16][O:17][C:18]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([C:11](=[O:12])[C:10]2[CH:14]=[CH:15][C:7]([O:6][CH3:5])=[CH:8][CH:9]=2)=[CH:27][C:19]=1[CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)CCc1ccc(OC)cc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)CCc1cc(C(=O)c2ccc(OC)cc2)c(OC)cc1OC
Temperature: 0 °C

Procedure:
52 g of aluminum trichloride are suspended in 200 ml of 1,2-dichloroethane and cooled to 0° C. Then, at this temperature, 66.5 g of 4-methoxybenzoyl chloride are added dropwise, followed by 94.7 g of ethyl 2,4-dimethoxyhydrocinnamate in 30 ml of 1,2-dichloroethane. The mixture is then heated at 50° C. with exclusion of moisture until the reaction is complete. The reaction mixture is then poured onto ice-water, and the organic phase is separated off, diluted with 200 ml of methylene chloride and then extracted with sodium bicarbonate solution and water. It is dried over magnesium sulfate and concentrated. A gray-brown solid remains and is immediately reacted further.
Reaction SMILES: CN(CCN(C)C)C.C([Li])CCC.[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.CN([CH:24]=[O:25])C>CCOCC>[Cl:14][C:15]1[C:16]([CH:24]=[O:25])=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: Clc1cccnc1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1ncccc1Cl
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a solution of TMEDA (660 μL, 2.58 mmol) in ether (20 mL) at −78° C. was added a solution of n-butyl lithium in ether (2.5 M, 1.76 mL, 4.40 mmol). After 30 minutes at −78° C., 3-chloropyridine (419 μL, 4.40 mmol) was added. After another 2 hours at −78° C., DMF (375 μL, 4.84 mmol) was added. After a further 2 hours at −78° C., the reaction was quenched with saturated aqueous NaHCO3 (20 mL), extracted with ether (4×15mL), dried (Na2SO4), filtered and concentrated in vacuo to give the crude oil. Purification by column chromatography on silica gel (Hexanes:EtOAc 4:1) afforded the title compound as a crystalline solid (168 mg, 27%). 1H NMR (CDCl3) 7.45 (dd, 1H, J=8.3, 4.4 Hz), 7.83 (dd, 1H, J=4.8, 1.4 Hz), 8.70 (dd, 1H, J=4.8, 1.5 Hz), 10.28 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([O:9][CH2:10][C:11]([CH3:13])=[CH2:12])[CH2:6]C=C)[CH3:2]>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:5]1[CH2:6][CH:13]=[C:11]([CH3:12])[CH2:10][O:9]1)=[O:14])[CH3:2]
Reactant: C=CCC(OCC(=C)C)C(=O)OCC
Solvent: ClCCl
Product: CCOC(=O)C1CC=C(C)CO1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 94 %

Procedure:
To a refluxing stirred solution of 2-(2-methyl-allyloxy)-pent-4-enoic acid ethyl ester (396 mg, 2.0 mmol) in CH2Cl2 (100 mL, 0.02 M solution) was added drop wise a solution of the tricyclohexylphosphine (1,3-Bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(benzylidine)ruthenium (IV)dichloride (85 mg, 0.1 mmol) in CH2Cl2 (3.0 mL). After 50 min, the reaction mixture was cooled to room temperature, concentrated and purified on silica gel bond elute using EtOAc/hexane (1:20) as an eluent furnished 5-methyl-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester (320 mg, 92% yield) as a brown oil. NMR 1H (CDCl3, 400 MHz): 5.51 (br s, 1H), 4.28-4.08 (m, 4H), 2.32 (brs, 3H), 1.29 (t, J=7.2, 3H).
Reaction SMILES: [O:1]([Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])S(C(F)(F)F)(=O)=O.[Br:16][C:17]1[CH:21]=[CH:20][O:19][C:18]=1[CH2:22]O.N1C=CC=CC=1>C(Cl)Cl>[Br:16][C:17]1[CH:21]=[CH:20][O:19][C:18]=1[CH2:22][O:1][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: OCc1occc1Br
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OCc1occc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 102.9 %

Procedure:
tert-Butyldimethylsilanyl triflate (17.13 g) was added slowly to a stirred, cooled solution of 3-bromo-2-hydroxymethylfuran (Intermediate 39, 10.1 g) in DCM (160 mL) and pyridine (9.57 g) while maintaining the temperature at 0° C. The mixture was allowed to warm to room temperature and stirred for 1 hour. The mixture was washed with aqueous citric acid solution, brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give 3-bromo-2-(tert-butyldimethylsilanyloxymethyl)furan (17.1 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:24](O)=[O:25])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].O[N:28]=[C:29]([NH2:31])[CH3:30]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][CH:11]([C:24]3[O:25][N:31]=[C:29]([CH3:30])[N:28]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1C
Reactant: CC(N)=NO
Product: Cc1noc(C2CC(c3ccc(C)c(C)c3)CN(C(=O)N3CCC(O)CC3)C2)n1

Procedure:
200 mg (0.54 mmol) of the compound from Example 128A and 62 mg (0.81 mmol) of N′-hydroxyacetamidine were reacted according to the General Method 2. Yield: 154 mg (69% of theory)
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([NH:12][CH2:13][CH2:14][CH3:15])[CH2:10][CH3:11]>CCOCC>[CH2:9]([N:12]([CH2:13][CH2:14][CH3:15])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:10][CH3:11]
Reactant: CCCNCCC
Reactant: BrCc1ccccc1
Solvent: CCOCC
Product: CCCN(CCC)Cc1ccccc1

Procedure:
An 11.9 ml portion of benzyl bromide and 41 ml of dipropylamine in ether were reacted as described in Example 3, giving 17.6 g of N,N-dipropylbenzenemethanamine as a clear liquid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:15][C@H:14]3[N:11]([C:12](=[O:19])[C@@H:13]3[C@H:16]([OH:18])[CH3:17])[C:10]=2[C:20]([O-:22])=[O:21])=[CH:5][CH:4]=1)#[N:2].[Na+].Cl[CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:15][C@H:14]3[N:11]([C:12](=[O:19])[C@@H:13]3[C@H:16]([OH:18])[CH3:17])[C:10]=2[C:20]([O:22][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:21])=[CH:5][CH:4]=1)#[N:2]
Reactant: ClCCN1CCOCC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3ccc(C#N)cc3)C[C@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCCN3CCOCC3)=C(c3ccc(C#N)cc3)C[C@H]12
Yield: 33 %

Procedure:
Sodium (5R,6S)-3-(4-cyanophenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.2 g) in dry DMF (4.0 ml) was ice-cooled. Thereto ware added tetrabutylammonium iodide (0.53 g), and 4-(2-chloroethyl)-morpholine (1M toluene, 8 mL), and the mixture was stirred. Thirty minutes later, after removal of the bath the mixture was stirred for 48 hours and thereto was added ethyl acetate. The mixture was washed succesively with aqueous phosphate buffer (pH 6.86), water and brine. The organic layer was dried over sodium sulfate, concentrated, and the residue was purified with silica gel column chromatography (chloroform:methanol=1:0→10:1) to give 2-morpholin-4-ylethyl(5R,6S)-3-(4-cyanophenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.10 g, yield 33%).