Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1.[O-:15][C:16]#[N:17].[Na+].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:16]([NH2:17])=[O:15])[CH:9]=1
Reactant: Cn1cccc1Cc1cccc(N)c1
Reactant: N#C[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccccc1
Product: Cn1cccc1Cc1cccc(NC(N)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
To a stirred solution of 4.4 g (23 mmol) of 1-methyl-2-(3'-aminobenzyl)pyrrole in 400 ml of benzene there were added 3.08 g (47 mmol) of sodium cyanate followed by the dropwise addition of a solution of 3.65 ml (47 mmol) of trifluoroacetic acid in 300 ml of benzene. When the addition was completed, the reaction mixture was stirred at room temperature for 1 hour further and then poured into 500 ml of saturated sodium carbonate solution. The organic phase was separated and the aqueous layer extracted with ethyl acetate (3×500 ml). The combined extracts were washed with water (1×500 ml), dried and evaporated under reduced pressure. The residue was purified by column chromatography on 500 g of silica gel, using methylene chloride-acetone (80:20) as eluant, thus obtaining 5.1 g (90%) of the title compound, 1-methyl-2-(3'-ureidobenzyl)pyrrole, which was recrystallized from acetone-hexane.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C([Sn](CCCC)(CCCC)[C:43]1[S:44][C:45]2[CH:51]=[CH:50][CH:49]=[CH:48][C:46]=2[N:47]=1)CCC.[F-].[Cs+]>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[S:44]1[C:45]2[CH:51]=[CH:50][CH:49]=[CH:48][C:46]=2[N:47]=[C:43]1[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:34])[CH3:35])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc2ccccc2s1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Br)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4nc5ccccc5s4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 130 °C
Yield: 45.2 %

Procedure:
A mixture of tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50.0 mg, 0.0895 mmol), 2-(tributylstannyl)-1,3-benzothiazole (76.0 mg, 0.179 mmol), bis (tri-tert-butylphosphine)palladium(0) (9.15 mg, 0.0179 mmol) and cesium fluoride (88.4 mg, 0.582 mmol) in dioxane (1.00 mL) was heated at 130° C. under microwave irradiation for 2 hours under nitrogen. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc (×3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (EtOAc/hexane=4:1→2:1→1:1) and PTLC (DCM/EtOAc=95:5) to afford desired product (24.8 mg, 45.2%) as pale yellow solid. 1HNMR (CDCl3) 500 MHz δ: 8.23 (dd, J=7.7, 1.4 Hz, 1H), 8.06-8.01 (m, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.53-7.38 (m, 5H), 7.36-7.29 (m, 2H), 7.17 (td, J=7.4, 1.1 Hz, 1H), 6.99-6.96 (m, 1H), 6.93-6.85 (m, 1H), 6.62 (dd, J=8.0, 4.6 Hz, 1H), 6.49-6.45 (m, 1H), 5.20 (br s, 1H), 2.69-2.26 (m, 4H), 2.21-2.09 (m, 1H), 1.97-1.85 (m, 1H), 1.41 (br s, 9H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[C:15](O)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.CCN=C=NCCCN(C)C>CC#N.CCOC(C)=O>[C:15]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1
Reactant: O=C(O)c1cccnc1
Reactant: CC(C)(C)OC(=O)NCCOCCN
Agent: CCN=C=NCCCN(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCOCCNC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.9 %

Procedure:
tert-Butyl 2-(2-aminoethoxy)ethylcarbamate (420, 2.06 mmol) was then taken up in CH3CN (20 mL) along with nicotinic acid (253 mg, 2.06 mmol) and EDCI (434 mg, 2.3 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. It was then diluted with EtOAc (20 mL), washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (9:1 CH2Cl2/MeOH) to afford tert-butyl 2-(2-(nicotinamido)ethoxy)ethylcarbamate (280 mg, 44%). MS calculated for C15H23N3O4: 309.17; found: [M+H]+310.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[CH3:26][C:27]1[CH:28]=[C:29]([Mg]Br)[CH:30]=[C:31]([CH3:33])[CH:32]=1>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:29]3[CH:30]=[C:31]([CH3:33])[CH:32]=[C:27]([CH3:26])[CH:28]=3)=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: Cc1cc(C)cc([Mg]Br)c1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Solvent: C1CCOC1
Product: Cc1cc(C)cc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)c1

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 90 mg (0.22 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 0.98 mL 0.5M 3,5-dimethylphenylmagnesium bromide. Yield: 66 mg of a white solid. LC-MSD, m/z for C24H19BrN2O2 [M+H]+=447.0, 449.0; HPLC retention time: 2.7 min.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14]Cl)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][N:22]2[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][OH:16])[CH2:20][CH2:21]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCN1CCNCC1
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Product: OCCN1CCN(CC2CN(Cc3ccccc3)CCO2)CC1
Temperature: 130 °C
Reaction time: 5 h

Procedure:
4-Benzyl-2-chloromethylmorpholine (15 g) and 4-(2-hydroxyethyl)piperazine (25 ml) are mixed, and the mixture is heated with stirring at 130° C. for five hours. After the reaction is complete, the mixture is extracted with chloroform, and the extract is dried over magnesium sulfate. The residue thus obtained is concentrated under reduced pressure to give 4-benzyl-2-[4-(2-hydroxyethyl)-1-piperazinyl]methylmorpholine (16 g).
Reaction SMILES: [C:1]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.C[OH:10].OO.[OH-].[Na+]>CCOCC>[CH:7]12[O:8][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][C:6]2=[O:10]
Reactant: CO
Reactant: O=C1C=CCCCC1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C1CCCCC2OC12
Reaction time: 1 h
Yield: 80 %

Procedure:
To a 0° C. solution of 50.0 g. (0.454 mmole) of cyclohept-2-en-1-one in 800 ml. of methanol was added 85 ml. of 30% hydrogen peroxide (0.75 mole) followed by the dropwise addition of 15 ml. of 6N sodium hydroxide (0.09 mole). The reaction was stirred for one hour and then added to 400 ml. ether-500 ml. petroleum ether. The ether extract was removed and the aqueous methanol phase extracted with four 500 ml. portions of petroleum ether and three 300 ml. portions of dichloromethane. The combined organic extracts were washed with three 800 ml. portions of saturated oodium chloride, dried over magnesium sulfate and evaporated under reduced pressure to an oil (53 g.). The crude oil was purified via vacuum distillation to yield 45.9 g. (80%) of the title compound as an oil. Caution: several forceful detonations have occurred during distillation of the crude product. (In general, however, the crude product is pure enough for further synthetic manipulations and distillation can be avoided.)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:16]=2)=[O:14])[CH:10]=[CH:9][C:8]=1[OH:26])[CH3:2].[Br:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:16]=2)=[O:14])[CH:10]=[CH:9][C:8]=1[O:26][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][Br:28])[CH3:2]
Reactant: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1O
Reactant: BrCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1OCCCCCCBr
Yield: 76 %

Procedure:
A mixture of 0.393 g (1.06 mmol) of 5-[[3-(ethoxycarbonyl)phenyl]carbonyl]-2-hydroxybenzenepropanoic acid ethyl ester, 2.06 g (8.44 mmol) of 1,6-dibromohexane, 0.882 g (6.39 mmol) of anhydrous granular potassium carbonate and 15 mL of 2-butanone was stirred and refluxed for 18.5 hrs. The resulting slurry was filtered with suction and the solids were washed thoroughly with ethyl acetate. The filtrate and washes were combined and concentrated in vacuo and the residue was purified by flash chromatography on 75 g of silica gel, eluting with 5:1 hexane-ethyl acetate, giving 0.43 g (75.8%) of the title compound as a colorless oil.
Reaction SMILES: [O:1]([C:8]1[C:13]2[C:14]([NH2:17])=[N:15][NH:16][C:12]=2[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18]([CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1(C)C=CC=CC=1>[O:1]([C:8]1[C:13]2[C:14]([NH:17][CH2:18][CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:22][CH2:21]3)=[N:15][NH:16][C:12]=2[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: Nc1n[nH]c2ccnc(Oc3ccccc3)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(CNc2n[nH]c3ccnc(Oc4ccccc4)c23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
To a stirred solution of the compound prepared in Example 434 (0.217 g,) in toluene (12 mL) was added tert-butyl 4-formylpiperidine-1-carboxylate (0.205 g). The mixture was evaporated in vacuo to remove water from imine formed. Sodium triacetoxyborohydride (0.244 g) was added, followed by acetic acid (0.4 mL). After stirring at room temperature for 1 hour, the reaction mixture was quenched with methanol slowly, to decompose excess borohydride, and then concentrated in vacuo. Ethyl acetate, was added to the residue and then washed with aqueous saturated sodium bicarbonate, dried, evaporated in vacuo to provide the title compound (0.262 g) with the following physical data.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:20](/[C:23](=[CH:29]\[CH:30]=[CH:31]\[C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1)/[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N+]=[N-]>C(OCC)C>[CH2:27]([O:26][C:24]([C:23](=[CH:29][CH:30]=[CH:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=1)[N:20]=[P:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:25])[CH3:28]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)/C(=C/C=C/c1ccc(C)cc1)N=[N+]=[N-]
Solvent: CCOCC
Product: CCOC(=O)C(=CC=Cc1ccc(C)cc1)N=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Following General Procedure J, triphenylphosphine (1.5 g, 5.8 mmol) ethyl (2Z,4E)-2-azido-5-(4-methylphenyl)penta-2,4-dienoate (Compound 45, 1.5 g, 5.8 mmol) in diethyl ether (50 ml) were reacted to produce the title compound as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[S:3]([C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([NH2:13])[C:7]=1[OH:14])(=[O:5])=[O:4].[Cl:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[N:24]=[C:25]=[O:26]>CN(C)C=O.C(OCC)(=O)C>[Cl:12][C:11]1[CH:10]=[CH:9][C:8]([NH:13][C:25]([NH:24][C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([Cl:23])[C:17]=2[Cl:16])=[O:26])=[C:7]([OH:14])[C:6]=1[S:3]([N:2]([CH3:15])[CH3:1])(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(N)c1O
Reactant: O=C=Nc1cccc(Cl)c1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2cccc(Cl)c2Cl)c1O
Yield: 44.9 %

Procedure:
A solution of N,N-dimethyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (80 mg, 0.32 mmol) and 2,3-dichlorophenylisocyanate (50 μL, 0.38 mmol) in 2 mL of N,N-dimethylformamide was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude material. Purification by column chromatography on silica gel, eluting with ethyl acetate/hexane (20/80, v/v), followed by recrystallization from ethyl acetate and hexane, gave the desired product (63 mg, 45%). 1H NMR (DMSO-d6): δ 10.51 (s, 1H), 9.34 (s, 1H), 9.27 (s, 1H), 8.29 (d, 1H), 7.32 (m, 2H), 7.16 (d, 1H), 2.87 (s, 6H).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].[K].[CH:16]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1)([CH3:18])[CH3:17]>>[CH2:1]([C:5]1[CH:6]=[C:7]([CH2:11][C:12]([O:14][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([O:19][CH:16]([CH3:18])[CH3:17])=[CH:21][CH:22]=2)=[O:13])[CH:8]=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cccc(CC(=O)O)c1
Reactant: CC(C)Oc1ccc(CCl)cc1
Agent: [K]
Product: CCCCc1cccc(CC(=O)OCc2ccc(OC(C)C)cc2)c1

Procedure:
3-Butylphenylacetic acid, potassium salt, is reacted with 4-isopropoxybenzyl chloride to obtain 4-isopropoxybenzyl 3-butylphenylacetate;
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[CH:20][C:12]2[C:13](=[O:19])[CH:14]=[C:15](C=O)[O:16][C:11]=2[C:10]=1[CH2:22][CH2:23][CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](O)(=O)[CH2:26][C:27]([OH:29])=[O:28]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:21]=[CH:20][C:12]2[C:13](=[O:19])[CH:14]=[C:15]([CH:25]=[CH:26][C:27]([OH:29])=[O:28])[O:16][C:11]=2[C:10]=1[CH2:22][CH2:23][CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1c(OCc2ccccc2)ccc2c(=O)cc(C=O)oc12
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Product: CCCc1c(OCc2ccccc2)ccc2c(=O)cc(C=CC(=O)O)oc12

Procedure:
7-Benzyloxy-4-oxo-8-propyl-4H-1-benzopyran-2-carboxaldehyde (3.2 g), from Example 1(c) and malonic acid (1.1 g) were heated in pyridine (15 ml) at 100° C. until gas evolution ceased. The mixture was then evaporated and the residue was extracted with sodium bicarbonate. Acidification gave the title acid. The same acid was also prepared by hydrolysis of the product of Example 1(d).
Reaction SMILES: [CH:1]1([NH:10][C:11]2[N:16]3[N:17]=[CH:18][C:19]([C:20](O)=[O:21])=[C:15]3[N:14]=[CH:13][C:12]=2[C:23]([N:25]2[CH2:30][CH2:29][CH:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:27][CH2:26]2)=[O:24])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:37][S:38]([NH2:41])(=[O:40])=[O:39]>>[CH:1]1([NH:10][C:11]2[N:16]3[N:17]=[CH:18][C:19]([C:20]([NH:41][S:38]([CH3:37])(=[O:40])=[O:39])=[O:21])=[C:15]3[N:14]=[CH:13][C:12]=2[C:23]([N:25]2[CH2:30][CH2:29][CH:28]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:27][CH2:26]2)=[O:24])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cnn2c(NC3CCc4ccccc43)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Product: CS(=O)(=O)NC(=O)c1cnn2c(NC3CCc4ccccc43)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 56.8 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2,3-dihydro-1H-inden-1-ylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (50 mg, 0.104 mmol) obtained in step 2 and methanesulfonamide (39 mg, 0.42 mmol), the title compound (33 mg, 57%) was obtained.
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:41])[C@@H:8]([NH2:40])[CH2:9][CH2:10][O:11][C:12]2[CH:21]=[C:20]3[C:15]([C:16]([O:22][C:23]4[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:37])[C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:25][CH:24]=4)=[CH:17][CH:18]=[N:19]3)=[CH:14][C:13]=2[O:38][CH3:39])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:42](=O)[CH:43]([CH3:45])[CH3:44].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH:1]1([O:6][C:7](=[O:41])[C@@H:8]([NH:40][CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:9][CH2:10][O:11][C:12]2[CH:21]=[C:20]3[C:15]([C:16]([O:22][C:23]4[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:37])[C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)=[CH:25][CH:24]=4)=[CH:17][CH:18]=[N:19]3)=[CH:14][C:13]=2[O:38][CH3:39])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)C=O
Reactant: COc1cc2c(Oc3ccc(NC(=O)c4ccccc4)cc3)ccnc2cc1OCC[C@H](N)C(=O)OC1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc2c(Oc3ccc(NC(=O)c4ccccc4)cc3)ccnc2cc1OCC[C@H](NCC(C)C)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To (S)-2-Amino-4-[4-(4-benzoylamino-phenoxy)-6-methoxy-quinolin-7-yloxy]-butyric acid cyclopentyl ester (37 mg, 0.066 mmol) in anhydrous methanol (1 ml) were added 100 μL of a 1 M solution of isobutyraldehyde in methanol and 1 drop of acetic acid. The reaction mixture was stirred at room temperature for 3 hours. Sodium cyanoborohydride (10.3 mg, 0.165 mmol) was then added and the reaction was left stirring 4 hours at room temperature, prior to concentration under vacuum. Purification by preparative HPLC afforded the title compound as a di-TFA salt (40 mg, 72% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][N:14]1[CH2:18]/[C:17](=[N:19]\[OH:20])/[C@H:16]([CH2:21][NH:22]C(=O)OCC3C=CC=CC=3)[CH2:15]1)=[N:9][C:8]([O:33][CH3:34])=[CH:7][CH:6]=2>[Pd].CO.C1COCC1>[NH2:22][CH2:21][C@@H:16]1[CH2:15][N:14]([CH2:13][CH2:12][C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([O:33][CH3:34])[N:9]=3)[N:4]=[CH:3][C:2]=2[F:1])[CH2:18]/[C:17]/1=[N:19]\[OH:20]
Reactant: COc1ccc2ncc(F)c(CCN3C/C(=N\O)[C@H](CNC(=O)OCc4ccccc4)C3)c2n1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2ncc(F)c(CCN3C/C(=N\O)[C@H](CN)C3)c2n1
Reaction time: 6 h

Procedure:
Phenylmethyl {[(3R,4Z)-1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-4-(hydroxyimino)-3-pyrrolidinyl]methyl}carbamate (0.180 g, 0.39 mmol) was dissolved in 1:1 (MeOH/THF) (10 mL). Catalytic 10% Palladium on carbon was added and the solution subjected to H at 55 PSI on a Parr shaker for 6 hours. The solution was filtered through a pad of celite and concentrated under reduced pressure. (0.174 g, quant.) LCMS: m/z 334.4 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([C:6](=O)[CH2:7][CH:8]2[CH2:12][CH2:11][CH2:10][C:9]2=O)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:26]=[C:22]([C:23]([OH:25])=[O:24])[C:21]([OH:27])=[CH:20][CH:19]=1>C(O)(=O)C>[Br:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]2[N:17]([C:18]3[CH:19]=[CH:20][C:21]([OH:27])=[C:22]([C:23]([OH:25])=[O:24])[CH:26]=3)[C:9]3[CH2:10][CH2:11][CH2:12][C:8]=3[CH:7]=2)=[CH:4][CH:3]=1
Reactant: O=C(CC1CCCC1=O)c1ccc(Br)cc1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Solvent: CC(=O)O
Product: O=C(O)c1cc(-n2c(-c3ccc(Br)cc3)cc3c2CCC3)ccc1O

Procedure:
A solution of 20.8 g. (0.07 mole) of 2-(p-bromophenacyl)cyclopentanone, 10.71 g. (0.07 mole) of 5-aminosalicylic acid, and 88 ml. of glacial acetic acid was heated under reflux under nitrogen for 31/2 hours, cooled and filtered. The collected solid was chromatographed on silica gel. The solid eluted with benzene was recrystallized from ethanol-water to provide tan crystals, m.p. 215°-216°.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8](Br)=[CH:7][C:6]=1[CH3:13])[CH:2]=[CH2:3].[Li]CCCC.C[O:20][C:21](=O)[O:22]C>C1COCC1>[CH2:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:21]([OH:22])=[O:20])=[CH:7][C:6]=1[CH3:13])[CH:2]=[CH2:3]
Reactant: C=CCOc1c(C)cc(Br)cc1C
Reactant: COC(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCOc1c(C)cc(C(=O)O)cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-allyloxy-5-bromo-1,3-dimethyl-benzene (23.6 g, 98.0 mmol) in THF (150 mL) is added at −75° C. a solution of n-BuLi (90 mL, 1.5 M in diethyl ether). The temperature remains at −75° C. The mixture is stirred for 30 min and then transferred via double-tip canula into a cooled (0° C.) solution of dimethylcarbonate (21.4 g, 238 mmol) in THF (90 mL). The mixture is stirred for 2 h at 0° C., then warmed to rt during 15 h. The solvent of the mixture is evaporated and re-evaporated with EtOH (200 mL) to remove most of the butylacetate side product. The mixture is taken up in 2 N aq. LiOH (150 mL) and EtOH (200 mL) and stirred at rt for 2 h then at 60° C. for 1 h. The EtOH is evaporated and the remaining mixture is diluted with 0.5 N aq. NaOH and extracted with diethyl ether (200 mL). The org. extract is washed with 1M aq. NaOH (5×50 mL) and the combined aq. washings are re-extracted with ether (100 mL). The aq. phase is acidified with 25% aq. HCl and extracted with DCM (5×50 mL). The combined org. extracts are dried over Na2SO4, filtered, evaporated and dried in vacuo at 60° C. for 15 h to give 4-allyloxy-3,5-dimethyl-benzoic acid (8.0) as a yellow-brown solid. LC-MS: tR=0.90 min.
Reaction SMILES: [ClH:1].C(OC([N:12]1[C:16](=[O:17])[CH2:15][CH2:14][C@H:13]1[C:18]([N:20]1[CH2:37][CH2:36][CH2:35][C@H:21]1[C:22]([NH:24][C@H:25]([CH:33]=[O:34])[CH2:26][CH2:27][CH2:28][NH:29][C:30](=[NH:32])[NH2:31])=[O:23])=[O:19])=O)C1C=CC=CC=1.[H][H]>CN(C)C=O.[Pd]>[ClH:1].[NH:12]1[C:16](=[O:17])[CH2:15][CH2:14][C@H:13]1[C:18]([N:20]1[CH2:37][CH2:36][CH2:35][C@H:21]1[C:22]([NH:24][C@H:25]([CH:33]=[O:34])[CH2:26][CH2:27][CH2:28][NH:29][C:30](=[NH:31])[NH2:32])=[O:23])=[O:19]
Reactant: [H][H]
Reactant: N=C(N)NCCC[C@@H](C=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CN(C)C=O
Product: N=C(N)NCCC[C@@H](C=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCC(=O)N1
Yield: 46.3 %

Procedure:
After N-benzyloxycarbonyl-L-pyroglutamyl-L-prolyl-L-argininal hydrochloride (0.081 g, 0.15 mmol) was dissolved in dimethlformamide (10 ml), palladium black (1 g) was added to the solution followed by catalytic hydrogenation at room temperature for 30 minutes in a hydrogen flow. After completion of the reaction, the catalyst was filtered off and ether was added to the residue. The precipitated crystals were filtered to give 0.028 g (46%) of L-pyroglutamyl-L-prolyl-L-argininal hydrochloride.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([CH3:11])[C:5]=1[CH3:12].[CH2:13]([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](Cl)=[CH:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[O:32][CH3:33])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])O.[Na+]>CS(C)=O>[CH2:13]([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([O:10][C:7]3[CH:8]=[CH:9][C:4]([NH2:3])=[C:5]([CH3:12])[C:6]=3[CH3:11])=[CH:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[O:32][CH3:33])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: Cc1c(N)ccc(O)c1C
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc2c(Oc3ccc(N)c(C)c3C)ccnc2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
Sodium hydride (60 wt %, 0.32 g) was added to dimethyl sulfoxide (6 ml), and the mixture was stirred at room temperature for 30 min. 4-Amino-2,3-dimethylphenol (1.10 g) was then added thereto, and the mixture was stirred at room temperature for 10 min. Next, 7-(benzyloxy)-4-chloro-6-methoxyquinoline (1.20 g) was added thereto, and the mixture was stirred at 110° C. for 6 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, followed by extraction with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel by development with chloroform/acetone (6/1) to give 0.78 g (yield 49%) of the title compound.