Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([OH:26])=O)=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[CH:31]1([CH2:34][O:35][C:36]2[N:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=2)[CH2:33][CH2:32]1.CCN(C(C)C)C(C)C>C1C=CC=CC=1.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([NH:42][C:39]3[CH:40]=[N:41][C:36]([O:35][CH2:34][CH:31]4[CH2:32][CH2:33]4)=[CH:37][CH:38]=3)=[O:26])=[CH:15][C:13]=2[N:14]=1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Reactant: Nc1ccc(OCC2CC2)nc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: CC1(C)Cc2c(c(C(=O)Nc3ccc(OCC4CC4)nc3)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Yield: 43.1 %

Procedure:
The title compound was prepared by following the procedure described for Example-108 using 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-15, 0.200 g, 0.533 mmol), thionyl chloride (2.0 mL), 6-(cyclopropylmethoxy)pyridin-3-amine (Intermediate-42, 0.132 g, 0.799 mmol), THF (5.0 mL), DIPEA (2 mL) and benzene (5 mL). The obtained crude product was purified by column chromatography on basic alumina eluting with 2.0% MeOH: DCM to afford 0.120 g of the desired product. 1HNMR (DMSO-d6): δ 0.37-0.74 (m, 4H), 1.20 (m, 1H), 1.53 (s, 6H), 3.06 (s, 2H), 3.74 (d, J=6.9 Hz, 2H), 6.40 (d, J=6.6 Hz, 1H), 7.27-7.30 (m, 2H), 7.39-7.41 (m, 2H), 7.50 (d, J=9.6 Hz, 1H), 8.25 (s, 1H), 9.27 (s, 1H), 11.00 (s, 2H); MS [M+H]+: 522.17.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH3:13][CH2:14][Mg+].[Br-].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1.C1COCC1>[NH2:2][C:1]1([C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=2)[CH2:14][CH2:13]1
Reactant: CC[Mg+]
Reactant: COC(=O)c1ccc(C#N)cc1
Agent: FB(F)F
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1ccc(C2(N)CC2)cc1
Reaction time: 0.5 h
Yield: 43 %

Procedure:
Methyl 4-cyanobenzoate (2.6 kg, 16.1 mol) was dissolved in 40 L of toluene at −25° C. and Ti(Oi-Pr)4 (4.73 L, 16.1 mol) was added over 5 min, followed by EtMgBr (10.5 L of a 3.07M solution in THF, 32.3 mol) over 2 hr. After aging for 30 min, BF3.OEt2 (4.1 L, 32 mol) was added over 40 min and the mixture was aged for another 40 min. The reaction was quenched by the addition of 40 L of 3N HCl. The layers were separated and the aqueous layer was washed with 13 L toluene. The aqueous layer was then extracted with 2-MeTHF (2×26 L and 2×13 L). The combined 2-MeTHF layers were washed with 3N NaOH and the pH of the NaOH layer adjusted to 9 before separation of the layers. The organic layer was washed with 13 L of brine. Yield=43%. 1H NMR (500 MHz, CDCl3): δ 8.00 (d, 2H), 7.35 (d, 2H), 3.95 (s, 3H), 1.25 (t, 2H), 1.10 (t, 2H).
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][C:12](=[O:14])[N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([O:23][CH3:24])[CH:16]=2)[C@H:10]1[CH2:25][CH3:26])(C(C)(C)C)(C)C.C(O)C.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:25]([C@H:10]1[C@H:9]([OH:8])[CH2:13][C:12](=[O:14])[N:11]1[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([O:23][CH3:24])[CH:16]=1)[CH3:26]
Reactant: CC[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)N1c1ccc(C#N)c(OC)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC[C@H]1[C@H](O)CC(=O)N1c1ccc(C#N)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.1 %

Procedure:
To a solution of 4-[(2S,3R)-3-(tert-butyldimethylsilyloxy)-2-ethyl-5-oxopyrrolidin-1-yl]-2-methoxybenzonitrile (1.04 g) in tetrahydrofuran (30 mL)-ethanol (15 mL) was added 6 mol/L hydrochloric acid (15 mL), and the mixture was stirred at room temperature for 18 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=5/1→0/1) to give the title compound as a colorless solid (yield: 528.3 mg, 73%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[C:4]([F:25])[CH:3]=1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:27].[K+].[K+]>C(#N)C.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[Cl:1][C:2]1[C:7]2[CH2:8][C:9](=[O:27])[CH2:10][O:11][C:6]=2[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[N:14]([CH3:23])[C:13]2=[O:24])=[C:4]([F:25])[CH:3]=1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3c2OCCC3)c1=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3c2OCC(=O)C3)c1=O
Yield: 97.9 %

Procedure:
By the method of Example 3, Step A, 0.5 gram (0.0013 mole) of 3-(5-chloro-3,4-dihydro-7-fluoro-2H-1-benzopyran-8-yl)-1-methyl-6-trifluoromethyluracil was reacted with 1.1 grams (0.0040 mole) of potassium persulfate and 0.3 gram (0.0013 mole) of copper(11) sulfate pentahydrate in 30 mL of acetonitrile and 30 mL of water, yielding 0.5 gram of 3-(5-chloro-3,4-dihydro-7-fluoro-2H-1-benzopyran-3-on-8-yl)-1-methyl-6-trifluoromethyluracil. The NMR spectrum was consistent with the proposed structure. This product was combined with another run of this reaction. The combined runs were subjected to column chromatography on silica gel, with 1:4 to 1:2 ethyl acetate:hexane as eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.8 gram of 3-(5-chloro-3,4-dihydro-7-fluoro-2H-1-benzopyran-4-on-8-yl)-1-methyl-6-trifluoromethyluracil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:24](O)=[O:25])[NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][CH2:14][C@H:15]([NH:16][C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:24][OH:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Agent: CCOC(=O)Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CO)CCCNC(=O)OCc1ccccc1

Procedure:
Preparation takes place in analogy to Example 83A from 1.0 g (2.73 mmol) of N5-[(benzyloxy)carbonyl]-N2-(tert-butoxycarbonyl)-L-ornithine in 35 ml of tetrahydrofuran with 0.276 g (2.73 mmol) of 4-methylmorpholine, 0.296 g (2.73 mmol) of ethyl chloroformate and 5.5 ml (5.5 mmol) of a 1M solution of lithium aluminum hydride in tetrahydrofuran. The product is purified by preparative HPLC (Kromasil, mobile phase acetonitrile/0.25% aqueous trifluoroacetic acid 5:95→95:5).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.C(=O)(O)[O-].[Na+].[SH:24][C:25]1[CH:26]=[CH:27][C:28]2[N:29]([N:31]=[N:32][N:33]=2)[N:30]=1.Cl>O.CC(C)=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([N:31]=[N:32][N:33]=4)[N:30]=3)[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Sc1ccc2nnnn2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3ccc4nnnn4n3)CS[C@H]12
Temperature: 50 °C
Reaction time: 0.12 h
Yield: 65.5 %

Procedure:
2.72 g of 7-aminocephalosporanic acid was suspended in 16 ml of water and 8 ml of acetone, and a suspension of 2.1 g of sodium bicarbonate in 16 ml of water was dropwise added thereto over a period of 7 minutes time. The inside temperature of a reactor was then increased to 50° C., and a suspension of 2.3 g of 6-mercaptotetrazolo[4,5-b]pyridazine in 35 ml of acetone was added dropwise thereto over a period of time of 10 minutes. The resulting mixture was refluxed for 6 hours at a stable inside temperature of reactor of 61° C. followed by allowing the refluxed mixture to stand. The pH of the solution was 8 and thereafter, the mixture was adjusted to a pH of 3.6 with 6 N hydrochloric acid under ice cooling, in which the pH was measured by means of a pH meter and then stirred for 1 hour. The precipitated crystals were filtered and dried over phosphorus pentoxide under reduced pressure to obtain 2.39 g of the titled compound having a melting point (decomposition) of 202° to 205° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:26][CH2:27][CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[CH:16][C:17]=3[O:19][CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:12]=[CH:11][N:10]=2)=[C:6]2[O:36][CH2:37][O:38][C:5]2=[CH:4][CH:3]=1.Cl[CH2:40][C:41]#[N:42].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:26][CH2:27][CH2:28][CH2:29][N:30]4[CH2:31][CH2:32][N:33]([CH2:40][C:41]#[N:42])[CH2:34][CH2:35]4)=[CH:16][C:17]=3[O:19][CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:12]=[CH:11][N:10]=2)=[C:6]2[O:36][CH2:37][O:38][C:5]2=[CH:4][CH:3]=1
Reactant: N#CCCl
Reactant: Clc1ccc2c(c1Nc1ncnc3cc(OCCCN4CCNCC4)cc(OC4CCOCC4)c13)OCO2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCN1CCN(CCCOc2cc(OC3CCOCC3)c3c(Nc4c(Cl)ccc5c4OCO5)ncnc3c2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 4-(6-chloro-2,3-methylenedioxyanilino)-7-(3-piperazin-1-ylpropoxy)-5-tetrahydropyran-4-yloxyquinazoline (1.3 g), 2-chloroacetonitrile (0.167 ml), sodium iodide (0.036 g), potassium carbonate (0.331 g) and DMF (15 ml) was stirred at ambient temperature for 5 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a 10:9:1 mixture of ethyl acetate, methylene chloride and methanol as eluent. There was thus obtained the title compound (0.69 g); NMR Spectrum: (CDCl3) 1.85-2.0 (m, 4H), 2.1 (m, 2H), 2.4-2.5 (m, 6H), 2.5-2.6 (m, 4H), 3.42 (s, 2H), 3.5-3.6 (m, 2H), 3.9-4.0 (m, 2H), 4.0-4.1 (m, 2H), 4.7 (m, 1H), 6.0 (s, 2H), 6.42 (s, 1H), 6.65 (d, 1H), 6.78 (d, 1H), 6.9 (d, 1H), 8.42 (s, 1H), 9.2 (s, 1H); Mass Spectrum: M+H+ 581 and 583.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[CH3:20][C:21]1[CH:22]=[C:23]([C:27]2[C:28]([C:33](O)=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:25][CH:26]=1>>[CH3:20][C:21]1[CH:22]=[C:23]([C:27]2[C:28]([C:33]([N:3]3[CH2:4][C@H:5]4[C@H:1]([CH2:6]4)[C@H:2]3[CH2:7][NH:8][C:9]([C:11]3[N:18]4[C:14]([S:15][CH:16]=[CH:17]4)=[N:13][C:12]=3[CH3:19])=[O:10])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: Cc1cccc(-c2ccccc2C(=O)O)c1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Product: Cc1cccc(-c2ccccc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 3′-Methyl-biphenyl-2-carboxylic acid. LC-MS (basic): tR=1.38 min; [M+H]+=471.2.
Reaction SMILES: OO.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][N:5]=1.Br[C:12]([F:19])([F:18])[C:13](OCC)=[O:14].S(=O)(=O)(O)O>CS(C)=O.O.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Fe+2]>[Br:10][C:7]1[CH:8]=[C:9]2[C:12]([F:19])([F:18])[C:13](=[O:14])[NH:3][C:4]2=[N:5][CH:6]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: OO
Solvent: CS(C)=O
Solvent: O
Product: O=C1Nc2ncc(Br)cc2C1(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 48.4 %

Procedure:
Hydrogen peroxide (30% aqueous, 2.019 mL, 19.77 mmol) was added dropwise to a stirred mixture of 2-amino-5-bromopyridine (1.71 g, 9.88 mmol), ferrocene (0.184 g, 0.988 mmol), and ethyl bromodifluoroacetate (3.82 mL, 29.7 mmol) in DMSO (50 mL) under an argon atmosphere. The reaction mixture was stirred at room temperature for 23 h. sulfuric acid (1.054 mL, 19.77 mmol) was added, and the reaction mixture was stirred at room temperature for 72 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel column chromatography eluting with EtOAc in hexanes to yield the title compound (1.19 g, 4.78 mmol, 48.4% yield) as a light purple solid. M+1: 248.9.
Reaction SMILES: [N+](C1C=CC(COC([NH:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18]([C@@H:20]3[CH2:24][C@H:23]([S:25][C:26]4[C@H:27]([CH3:50])[C@@H:28]5[C@@H:45]([C@H:46]([OH:48])[CH3:47])[C:44](=[O:49])[N:29]5[C:30]=4[C:31]([O:33]CC4C=CC([N+]([O-])=O)=CC=4)=[O:32])[CH2:22][N:21]3C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=[O:19])[CH2:14]2)=O)=CC=1)([O-])=O.[ClH:66]>O1CCCC1.O>[ClH:66].[NH2:12][C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([C@@H:20]2[CH2:24][C@H:23]([S:25][C:26]3[C@H:27]([CH3:50])[C@@H:28]4[C@@H:45]([C@H:46]([OH:48])[CH3:47])[C:44](=[O:49])[N:29]4[C:30]=3[C:31]([OH:33])=[O:32])[CH2:22][NH:21]2)=[O:19])[CH2:14]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@H](NC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CC[C@H](N)C4)C3)[C@H](C)[C@H]12

Procedure:
1.0 g of 4-nitrobenzyl (1R, 5S, 6S)-2-{(2S, 4S)-2-[(3S)-3-(4-nitrobenzyloxycarbonyl)aminopyrrolidin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 30 ml of a 2:1 by volume mixture of tetrahydrofuran and water, after which 1.0 ml of 1N aqueous hydrochloric acid was added, and the mixture was hydrogenated by bubbling hydrogen through in at room temperature for 2 hours in the presence of 1.5 g of 10% w/w palladium-on-charcoal. The catalyst was filtered off, and the filtrate was washed with diethyl ether. The washed aqueous solution was concentrated by evaporation under reduced pressure, and the residue was purified by reverse phase column chromatography through 19 ml of Cosmo Sil 75C18 -PREP (a trade mark for a product of Nacalai Tesque), using water as the eluent. Those fractions containing the title compound were combined, concentrated by evaporation under reduced pressure and lyophilized to give 169 mg of the title compound as a powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH2:15][C:16]([OH:18])=O)[CH:12]=[CH:13][CH:14]=1)=[O:4].[CH2:23]([NH:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(Cl)CCl.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[CH2:30]([N:29]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:16](=[O:18])[CH2:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH2:7][C:6]1[CH:19]=[CH:20][CH:21]=[CH:22][C:5]=1[C:3]([O:2][CH3:1])=[O:4])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCCCCCNCc1ccccc1
Reactant: COC(=O)c1ccccc1COc1cccc(CC(=O)O)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: ClCCCl
Product: CCCCCCN(Cc1ccccc1)C(=O)Cc1cccc(OCc2ccccc2C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(3-{[2-(Methoxycarbonyl)benzyl]oxy}phenyl)acetic acid (60 mg, 0.2 mmol) was dissolved in DCM (2 ml), N-hexylbenzylamine (46 mg, 0.24 mmol) was added, then EDC (46 mg, 0.24 mmol) was added and then DMAP (29.3 mg, 0.24 mmol) was added. The mixture was stirred at room temperature overnight. 1% hydrochloric acid (1 ml) and water (1 ml) were added into the mixture. The two phases were separated by using a Whatman Filter Tube. The obtained organic portion was evaporated in vacuum and 59 mg crude oil product was left. It was then used directly in next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:7][C:6](=[CH:16][N:17](C)C)[C:5]2=[O:20].[C:21]([O:25][C:26]([N:28]([CH3:30])N)=[O:27])([CH3:24])([CH3:23])[CH3:22].C(O)(=O)C>CO.O1CCCC1>[C:21]([O:25][C:26]([N:28]([CH3:30])[NH:17][CH:16]=[C:6]1[C:5](=[O:20])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:7]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: CCC(=O)N1CC(=CN(C)C)C(=O)c2cc(Cl)ccc21
Reactant: CN(N)C(=O)OC(C)(C)C
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCC(=O)N1CC(=CNN(C)C(=O)OC(C)(C)C)C(=O)c2cc(Cl)ccc21
Reaction time: 8 h
Yield: 78 %

Procedure:
A solution of 6-chloro-3-dimethylaminomethylene-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (2.00 g), 1-tert-butoxycarbonyl-1-methylhydrazine (1.50 g) and acetic acid (1.20 ml) in methanol (100 ml) and tetrahydrofuran (100 ml) was refluxed for 9 hours with stirring. 1-tert-Butoxycarbonyl-1-methylhydrazine (1.50 g) was added to the mixture and the stirring was continued for 8 hours at reflux conditions. After the solvent was evaporated in vacuo, saturated aqueous sodium hydrogen carbonate (15 ml) was added to the mixture and extracted with ethyl acetate (30 ml). The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue (3.90 g) was chromatographed on silica gel by eluting with chloroform to give 3-(2-tert-butoxycarbonyl-2-methylhydrazino)methylene-6-chloro-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (2.10 g) as yellow amorphous.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[N:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C(N(C(C)C)CC)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.Cl.[CH3:58][N:59]([C@H:72]1[C:81]2[C:76](=[CH:77][CH:78]=[CH:79][CH:80]=2)[CH2:75][CH2:74][CH2:73]1)[C:60]([C:62]1[N:63]=[C:64]([CH2:67][CH2:68][CH2:69][NH:70][CH3:71])[S:65][CH:66]=1)=[O:61]>C(#N)C>[CH3:58][N:59]([C@H:72]1[C:81]2[C:76](=[CH:77][CH:78]=[CH:79][CH:80]=2)[CH2:75][CH2:74][CH2:73]1)[C:60]([C:62]1[N:63]=[C:64]([CH2:67][CH2:68][CH2:69][N:70]([CH3:71])[C:8](=[O:10])[CH2:7][N:6]2[C:2]([CH3:1])=[CH:3][C:4]([C:11]([F:14])([F:13])[F:12])=[N:5]2)[S:65][CH:66]=1)=[O:61]
Reactant: CNCCCc1nc(C(=O)N(C)[C@@H]2CCCc3ccccc32)cs1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N(C)CCCc1nc(C(=O)N(C)[C@@H]2CCCc3ccccc32)cs1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.2 %

Procedure:
To a solution of (5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (0.053 g, 0.25 mmol) in acetonitrile (3 mL) was added diisopropylethylamine (0.17 mL, 1.01 mmol), followed by 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (0.11 g, 0.3 mmol). After stirring 15 min at RT, 2-(3-methylamino-propyl)-thiazole-4-carboxylic acid methyl-(R)-1,2,3,4-tetrahydro-naphthalen-1-yl-amide hydrochloride salt (0.096 g, 0.25 mmol) was added to the reaction mixture. After stirring overnight at RT, solvent was evaporated and the resulting yellow oil was dissolved in ethylacetate (20 mL), washed with saturated aqueous sodium bicarbonate solution (30 mL), 1M HCl solution (10 mL), and brine (10 mL). The organic layer was dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude mixture was purified by column chromatography on silica gel (ethylacetate/cyclohexane 7:3) to give 2-(3-{methyl-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-amino}-propyl)-thiazole-4-carboxylic acid methyl-(R)-1,2,3,4-tetrahydro-naphthalen-1-yl-amide (Compound No. 1.d.55, 83 mg, 61%). 1H-NMR (400 MHz, CDCl3): δ=7.75-7.80 (s, 1H (conformers)), 7.31-7.29 (m, 1H), 7.20-7.06 (m, 3H), 6.35-6.25 (s, 1H (conformers)), 6.05-5.55 (m, 1H (conformers)), 5.05-4.75 (s, 2H (conformers)), 3.55-3.46 (m, 2H), 3.10-2.90 (s, 3H (conformers)), 3.08-3.05 (m, 1H), 2.90-2.75 (s, 3H (conformers)+m, 3H), 2.30-2.20 (s, 3H (conformers)), 2.15-1.61 (m, 6H). MS: m/z=534 (M+1).
Reaction SMILES: [OH:1][CH:2]([CH2:14][CH3:15])[CH:3]=[C:4]1C(=O)OC(C)(C)OC1=O.CC1(C)OC(=O)CC(=O)O1.C(Cl)(=O)CC.[C:31]([OH:40])(=[O:39])[C:32]1[C:33](=[CH:35][CH:36]=[CH:37][CH:38]=1)[NH2:34].C(OC(=O)C)(=O)C>C1C=CC=CC=1.O1CCCC1.CC(C)=O>[O:1]=[C:2]([CH2:14][CH3:15])[CH2:3][C:4]1[O:39][C:31](=[O:40])[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: CCC(O)C=C1C(=O)OC(C)(C)OC1=O
Agent: CC1(C)OC(=O)CC(=O)O1
Agent: CCC(=O)Cl
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: c1ccccc1
Product: CCC(=O)Cc1nc2ccccc2c(=O)o1
Temperature: 25 °C
Yield: 33 %

Procedure:
To a solution in a mixture of benzene (100 mL)/acetone (100 mL) of the crude 5-(2-hydroxybutylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione which was previously prepared from Meldrum's acid (57.7 g, 0.40 mol) and propionyl chloride(37.0 g, 0.40 mol) according to the methods described in Synthesis, p. 1213 (1992) and Org. Synth., vol. 63, p. 198 (1985), anthranilic acid (45.8 g, 0.33 mol) was added and the mixture was heated under reflux for 3 hours. The solution was cooled to room temperature and concentrated under reduced pressure. The residue was suspended in a mixture of acetic anhydride (68.1 g, 0.667 mol) and tetrahydrofuran (150 mL), and the suspension was heated under reflux for 30 minutes. The solution was cooled to room temperature and concentrated under reduced pressure, and the residue thus obtained was purified by silica gel column chromatography (ethyl acetate:hexane=2:8) to give the title compound (28.4 g, 33% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1B(O)O.[CH3:12][O:13][C:14]([C:16]1[CH:17]=[C:18](I)[CH:19]=[C:20]([CH:24]=1)[C:21]([OH:23])=[O:22])=[O:15].C(=O)([O-])[O-].[K+].[K+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][O:13][C:14]([C:16]1[CH:24]=[C:20]([CH:19]=[C:18]([C:3]2[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=2[Cl:1])[CH:17]=1)[C:21]([OH:23])=[O:22])=[O:15]
Reactant: COC(=O)c1cc(I)cc(C(=O)O)c1
Reactant: OB(O)c1cc(Cl)ccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Product: COC(=O)c1cc(C(=O)O)cc(-c2cc(Cl)ccc2Cl)c1
Temperature: 40 °C
Reaction time: 4 h
Yield: 50.5 %

Procedure:
The mixture of 2,5-dichlorophenyl-dihydroxyborane (9.35 g), 5-methoxycarbonyl-3-iodobenzoic acid (10 g), potassium carbonate (14.0 g) and palladium(II) acetate (0.073 g) in water (200 ml) was stirred at 40° C. for four hours. Undissolved material was filtered, washed with water (100 ml), suspended in water (150 ml) and adjusted to pH 2.0 with 6N hydrochloric acid. The mixture was extracted two times with a mixture of ethyl acetate (120 ml) and tetrahydrofuran (60 ml), washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residual crystalline was washed with n-hexane to give 3-methoxycarbonyl-5-(2,5-dichlorophenyl)benzoic acid (5.36 g, 50.4%).