Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH:9]=[C:8](I)[N:7]=[CH:6]2)[CH2:3][CH2:2]1.C([Mg]Cl)(C)C.[CH2:16]([Sn:20]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])Cl)[CH2:17][CH2:18][CH3:19]>C1COCC1>[CH:1]1([CH2:4][N:5]2[CH:9]=[C:8]([Sn:20]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:16][CH2:17][CH2:18][CH3:19])[N:7]=[CH:6]2)[CH2:3][CH2:2]1
Reactant: Ic1cn(CC2CC2)cn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn(CC2CC2)cn1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 78.2 %

Procedure:
In a round bottomed flask 1-cyclopropylmethyl-4-iodo-1H-imidazole (570 mg, 2.3 mmol) was dissolved in THF (10 mL). The solution was cooled to 0° C. and isopropylmagnesium chloride (2.0 M in THF, 1.15 mL, 2.3 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 1.5 h. Tributylchlorostannane (0.62 mL, 2.3 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated NH4Cl solution and extracted with ethyl acetate (3×). The combined organics were washed with brine, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 20% to 50% EtOAc/heptane (containing 0.5% triethylamine) to isolate 740 mg (78%) of 1-cyclopropylmethyl-4-tributylstannanyl-1H-imidazole as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([C:13]([OH:15])=O)[CH2:10]2)=[CH:5][CH:4]=1.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][C:18]=1[C:24]([F:27])([F:26])[F:25].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:13]([CH:9]2[CH2:8][CH2:7][C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:10]2)=[O:15])=[CH:19][C:18]=1[C:24]([F:25])([F:26])[F:27]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: COc1ccc2c(c1)CC(C(=O)O)CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CC(C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1)CC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.2 %

Procedure:
To a solution of 7-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (250 mg, 1.21 mmol), and 4-chloro-3-(trifluoromethyl)aniline (260 mg, 1.33 mmol) in DMF (12.0 mL) was added DIPEA (1.06 mL, 6.07 mmol) and then HATU (508 mg, 1.34 mmol). The solution was allowed to stir at rt for 18 h. 1N HCl was added and the mixture was extracted with EtOAc. The organic solution was washed with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography to give N-[4-chloro-3-(trifluoromethyl)phenyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide as a white solid (233 mg, 50%). LCMS: (FA) ES+ 384.1, ES− 382.1.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:23]=[CH:22][C:17]3[B:18]([OH:21])[O:19][CH2:20][C:16]=3[CH:15]=2)[CH:10]=[CH:9][C:8]=1[C:24]#[N:25])C.[Li+].[OH-].O.Cl>C1COCC1>[C:24]([C:8]1[CH:9]=[CH:10][C:11]([O:13][C:14]2[CH:23]=[CH:22][C:17]3[B:18]([OH:21])[O:19][CH2:20][C:16]=3[CH:15]=2)=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:26])=[O:3])#[N:25]
Reactant: CCOC(=O)COc1cc(Oc2ccc3c(c2)COB3O)ccc1C#N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(Oc2ccc3c(c2)COB3O)cc1OCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
To a clear solution of [2-cyano-5-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-phenoxy]-acetic acid ethyl ester ((D38), 90 mg, 0.25 mmol) in THF (20 mL) was added LiOH (15.3 mg, 0.76 mmol) and water (5 mL). The resulting mixture was stirred at room temperature for 2 hours. Then 1 N HCl was slowly added to pH 2. The mixture was evaporated under vacuum. The residue was purified with reverse phase chromatography, eluting from 5% MeOH/H2O to 90% MeOH/H2O, afforded 48 mg of the title compound in 58% yield. 1H NMR 400 MHz (CD3OD) δ: 7.70 (d, J=7.8 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.09 (s, 1H), 7.05 (dd, J=1.9, 8.21 Hz, 1H), 6.66 (d, J=1.9 Hz, 1H), 6.63 (dd, J=1.9, 8.6 Hz, 1H), 5.06 (s, 2H), 4.78 (s, 2H); MS (ES) m/z: 326 (M+H)+; HPLC purity: 96.33% (220 nm), 96.44% (254 nm).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[H-].[Na+].[OH:11][C:12]1[CH:17]=[CH:16][O:15][CH2:14][CH:13]=1>CN(C)C=O.[Cl-].[Na+].O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:3][CH:4]=1
Reactant: OC1=CCOC=C1
Reactant: Brc1ccc(Br)nc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(OC2CCOCC2)nc1
Temperature: 0 °C
Yield: 87.2 %

Procedure:
A solution of 2,5-dibromopyridine (9.5 g, 40 mmol) in N,N-dimethylformamide (100 mL) was treated with sodium hydride (60% dispersion in mineral oil, 2.4 g, 60 mmol). The mixture was cooled to 0° C. and 4-hydroxypyran (3.8 mL, 40 mmol) was added slowly. The resultant mixture was stirred at room temperature for 24 hours, then was added to dilute brine solution and was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, was filtered, and the solvent was removed in vacuo. The residue was purified by silica gel chromatography (40:1 hexanes-ethyl acetate) to afford 9.0 g (87% yield) of the title compound. 13C NMR (100 MHz, CDCl3) d 162.0, 147.6, 141.5, 113.5, 111.7, 70.3, 65.7, 32.1; MS (AP/Cl) 258.2, 260.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:9]=[C:8]([CH2:10]OS(C)(=O)=O)[C:7]=2[CH:16]=1.[CH2:17]([O:19][C:20]([CH:22]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]1)=[O:21])[CH3:18].C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH2:17]([O:19][C:20]([CH:22]1[CH2:27][CH2:26][CH2:25][N:24]([CH2:10][C:8]2[C:7]3[CH:16]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[CH:9]=2)[CH2:23]1)=[O:21])[CH3:18]
Reactant: CCOC(=O)C1CCCNC1
Reactant: COc1ccc2c(c1)C(COS(C)(=O)=O)=C2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCCN(CC2=Cc3ccc(OC)cc32)C1
Reaction time: 18 h

Procedure:
To a solution of 7.27 g (30 mmol) of methanesulphonic acid (5-methoxybenzocyclobuten-1-yl)methyl ester in 60 ml of dimethylformamide there are added first 5.66 g (36 mmol) of piperidine-3-carboxylic acid ethyl ester and then 9.70 g (75 mmol) of N-ethyl-N,N-diisopropylamine. The mixture is stirred at 60° for 18 hours and, after cooling,is concentrated by evaporation under a high vacuum. The residue is taken up in diethyl ether and washed with water, and the organic phase is extracted with 2N hydrochloric acid. The hydrochloric acid extracts are combined, rendered alkaline at reduced temperature with concentrated sodium hydroxide solution and extracted with dichloromethane. The combined organic phases are dried over sodium sulphate and concentrated to dryness by evaporation under reduced pressure. 1-[(5-methoxybenzocyclobuten-1-yl)methyl]-piperidine-3-carboxylic acid ethyl ester is obtained in the form of a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)Br)=[CH:4][CH:3]=1.[C:20]1([CH2:26][CH2:27][CH2:28][C:29]([NH2:31])=[S:30])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:31]=[C:29]([CH2:28][CH2:27][CH2:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:30][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: NC(=S)CCCc1ccccc1
Reactant: CSc1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CSc1ccc(-c2sc(CCCc3ccccc3)nc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 95.3 %

Procedure:
To a solution of 2-bromo-1-(4-fluorophenyl)-2-(4-methylthiophenyl)ethanone (Example 1, step 3) (0.100 g, 0.295 mmol) in ethanol (3 mL) in a 10 mL round bottom flask was added 4-phenylthiobutyramide from step 1 (0.055 g, 0.310 mmol) and the mixture heated to reflux overnight. The reaction was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with Na2CO3 (10% solution), brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude thiazole was flash chromatographed (9:1, hexane:ethyl acetate) yielding 4-(4-fluorophenyl)-5-(4-methylthiophenyl)-2-(3-phenylpropyl)thiazole (0.118 g, 95%) as crystalline solid: mp 62°-63° C.; 1HNMR (CDCl3) 300 mHz 7.49 (d of d, J=5.52 and 8.85, 2H), 7.33-7.14 (m, 9H), 6.98 (t, J=8.85, 2H), 3.05 (t, J=7.74, 2 H), 2.82 (t, J=7.74 Hz, 2H), 2.49 (s, 3H), 2.18 (m, 2 H); MS (FAB) m/z 420 (MH+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[CH2:7]([NH:10][CH2:11][CH:12]=[CH2:13])[CH:8]=[CH2:9]>>[CH2:7]([N:10]([CH2:11][CH:12]=[CH2:13])[C:4](=[O:5])[CH2:3][CH2:2][Cl:1])[CH:8]=[CH2:9]
Reactant: C=CCNCC=C
Reactant: O=C(Cl)CCCl
Product: C=CCN(CC=C)C(=O)CCCl

Procedure:
comprises first reacting 3-chloropropionyl chloride (CPC) with diallylamine to form N,N-diallyl-3-chloropropaneamide, then reacting this product with RF-iodide followed by eliminating HCl and Hl by dehydrohalogenating with a base such as an alkali metal hydroxide. The product of the formula IIa is then washed with water followed by separating the aqueous layer.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:28]([CH3:30])[CH3:29]>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH:28]([CH3:30])[CH3:29])[CH2:20][CH2:19]1
Reactant: CC(C)I
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCNCC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCN(C(C)C)CC3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(4-piperidinyl)propyl]-9H-purin-6-amine and 2-iodopropane.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:25])[N:11]([C:18](N2C=CN=C2)=[O:19])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH2:26]([OH:32])[C@H:27]([OH:31])[C:28]([OH:30])=[O:29].C(O)(C(F)(F)F)=O>C1COCC1>[C:28]([CH:27]([OH:31])[CH2:26][O:32][C:18]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)/[C:9](=[CH:8]/[C:3]2[NH:4][C:5]([CH3:7])=[CH:6][C:2]=2[CH3:1])/[C:10]1=[O:25])=[O:19])([OH:30])=[O:29]
Reactant: O=C(O)[C@@H](O)CO
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)n3ccnc3)c3ccccc32)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)OCC(O)C(=O)O)c3ccccc32)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 8.1 %

Procedure:
A reaction mixture of 3-[1-(3,5-dimethyl-1h-pyrrol-2-yl)-meth-(z)-ylidene]-1-(imidazol-1-ylcarbonyl)-1,3-dihydro-indole-2-one (166 mg, 0.5 mmol), L-glyceric acid (432 mg, 1.5 mmol), and TFA (399 mg, 3.5 mmol) in 3 mL of THF was stirred at room temperature for 4 h and concentrated. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (1:4) followed by 1% of acetic acid in ethylacetate-hexane (1:1) to afford 15 mg (8%) of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-carboxy-2-hydroxy-ethyl ester as a red solid. MS m/z (relative intensity, %) 371 (100, [M+1]+.).
Reaction SMILES: [C:1](OC)([O:5][CH3:6])([O:3]C)[CH3:2].C(O)(=O)CC.[CH2:14]=[CH:15][CH:16](O)[CH2:17][CH:18]=[CH2:19]>COC(C)(C)C>[C:1]([O:5][CH3:6])(=[O:3])[CH2:2][CH2:14]/[CH:15]=[CH:16]/[CH2:17][CH:18]=[CH2:19]
Reactant: COC(C)(OC)OC
Reactant: C=CCC(O)C=C
Solvent: COC(C)(C)C
Solvent: CCC(=O)O
Product: C=CC/C=C/CCC(=O)OC
Temperature: 120 °C
Reaction time: 2 h

Procedure:
78.0 g (about 0.71 mol) of 1,5-hexadien-3-ol, obtained by a Grignard reaction from allylmagnesium bromide and acrolein, were dissolved in 198.0 g (1.65 mol) of trimethyl orthoacetate and 3.0 g (0.04 mol) of propionic acid were then added. The reaction mixture was heated to 120° C. and the methanol formed during the reaction was distilled off over a 15 cm Widmer column. After 2 hours, the reaction mixture was held at 130° C. for a further 1 hour to complete the reaction and was then cooled to room temperature, diluted with 500 ml of tert-butyl methyl ether and the solution was washed twice with 100 ml of saturated sodium bicarbonate solution, dried with sodium sulphate and concentrated. Distillation of the resulting 128 g of crude product over a 20 cm Widmer column gave 51.6 g of olfactorily good methyl (E)-4,7-octadienoate of boiling point 76° C./17 mbar and with a purity of about 98%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:21])[CH2:17][C:18]([OH:20])=O)=[CH:11][C:10]=2[F:22])[CH:5]=[CH:4][N:3]=1.[ClH:23].[NH2:24][C@@H:25]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:26]([NH2:28])=[O:27]>>[ClH:23].[NH2:28][C:26](=[O:27])[C@@H:25]([NH:24][C:18](=[O:20])[CH2:17][C:16]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=2)=[C:10]([F:22])[CH:11]=1)=[O:21])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NC(=O)[C@@H](N)c1ccccc1
Reactant: Nc1cc(Oc2ccc(NC(=O)CC(=O)O)cc2F)ccn1
Agent: Cl
Product: NC(=O)[C@@H](NC(=O)CC(=O)Nc1ccc(Oc2ccnc(N)c2)c(F)c1)c1ccccc1
Yield: 52.8 %

Procedure:
3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoic acid (30 mg, 0.10 mmol) was coupled with (S)-2-amino-2-phenylacetamide hydrochloride (Acros, 28 mg, 0.15 mmol) in a manner similar to that which is described in Step C of Example 1 to give (S)—N1-(2-amino-2-oxo-1-phenylethyl)-N3-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)malonamide, hydrochloride salt (25 mg, 53% yield). 1H NMR (DMSO-d6) δ 10.68 (s, 1H), 8.80 (d, 1H, J=8.0 Hz), 7.96 (d, 1H, J=7.5 Hz), 7.77-7.90 (m, 4H), 7.20-7.45 (m, 8H), 6.70 (m, 1H), 6.12 (s, 1H), 5.39 (d, 1H, J=7.5 Hz), 3.48 (d, 1H, J=15.0 Hz), 3.41 (d, 1H, J=15.0 Hz); MS (ESI+) m/z 438.26 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([F:13])[CH:7]=1.[C:17]([NH2:20])(=[S:19])[CH3:18]>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:17]([CH3:18])[S:19][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([F:13])[CH:7]=1)=[O:16]
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)c(F)c1
Reactant: CC(N)=S
Product: COC(=O)c1nc(C)sc1-c1ccc(F)c(F)c1

Procedure:
prepared by reaction of 3-chloro-3-(3,4-difluoro-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.92 min; [M+H]+=270.3.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:24])=[CH:9]/[S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([NH2:23])(=[O:22])=[O:21])(=[O:12])=[O:11])=[CH:4][CH:3]=1.ClC1C=CC(C(=C)CS(NC2C=CC=CC=2S(N)(=O)=O)(=O)=O)=CC=1.[H][H]>CO.[Pd]>[C:5]1([CH:8]([CH3:24])[CH2:9][S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([NH2:23])(=[O:22])=[O:21])(=[O:11])=[O:12])[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: C/C(=C\S(=O)(=O)Nc1ccccc1S(N)(=O)=O)c1ccc(Cl)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: C=C(CS(=O)(=O)Nc1ccccc1S(N)(=O)=O)c1ccc(Cl)cc1
Solvent: CO
Product: CC(CS(=O)(=O)Nc1ccccc1S(N)(=O)=O)c1ccccc1
Yield: 32 %

Procedure:
A mixture of 2-[[(E)-2-(4-chlorophenyl)prop-1-enyl]sulfonylamino]benzenesulfonamide and 2-[2-(4-chlorophenyl)prop-2-enylsulfonylamino]benzenesulfonamide (40 mg, 0.11 mmol) was dissolved in methanol (3 ml) and subjected to the H-cube (1 ml/min, full hydrogen. 10% Pd/C, 2 runs). The product obtained was purified by preparative HPLC (XTerra MS C8 column, acetonitrile/ammonium acetate buffer) to give the title compound (13 mg, 32%) as a white solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])(=O)=O.[CH2:21]([NH:23][CH:24]1[CH2:26][CH2:25]1)[CH3:22]>>[CH:24]1([N:23]([CH2:21][CH3:22])[CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:12])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:26][CH2:25]1
Reactant: CS(=O)(=O)OCCCCNC(=O)OCc1ccccc1
Reactant: CCNC1CC1
Product: CCN(CCCCNC(=O)OCc1ccccc1)C1CC1

Procedure:
Following the general procedure of Example 4, Step 2, and making non-critical variations but using 4-(benzyloxycarbonylamino)butyl methanesulfonate and commercially available N-ethylcyclopropanamine, benzyl 4-(cyclopropyl(ethyl)amino)butylcarbamate was obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:11][C@H:12]([CH2:18][NH:19][CH3:20])[CH2:13][C:14](OC)=[O:15])[CH:6]=[CH:7][C:8]=1[C:9]#[N:10].C([O-])([O-])=O.[K+].[K+]>CC#N.CO>[Cl:2][C:3]1[CH:4]=[C:5]([NH:11][C@H:12]2[CH2:13][C:14](=[O:15])[N:19]([CH3:20])[CH2:18]2)[CH:6]=[CH:7][C:8]=1[C:9]#[N:10]
Reactant: CNC[C@H](CC(=O)OC)Nc1ccc(C#N)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: CN1C[C@@H](Nc2ccc(C#N)c(Cl)c2)CC1=O
Temperature: 68 °C
Reaction time: 0.33 h
Yield: 81.2 %

Procedure:
A mixture of methyl (3S)-3-[(3-chloro-4-cyanophenyl)amino]-4-(methylamino)butanoate, hydrochloride (15.6 g., 49 mmole) and K2CO3 (325 mesh, 15.0 g, 110 mmole) in MeCN (120 mL) and MeOH (30 mL) was heated with stirring at 68° C. for 20 min. The solvents were evaporated, and the residue partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (2×), the combined EtOAc extracts were washed with H2O and brine, dried (MgSO4) and the solvent evaporated. The crude product (10.3 g) was triturated with Et2O, chilled and the solid filtered to give the titled compound (9.93 g, 81%). LC-MS (ES) m/e 250 (M+H)+.
Reaction SMILES: C1(C)C=CC(S(N[C@H](C(O)=O)C)(=O)=[O:8])=CC=1.ON1C2C=CC=CC=2N=N1.[CH:27]1([N:33]=[C:34]=[N:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.COC1C=C(O)C=C(OC)C=1.C(N(CC)CC)C>C(OCC)(=O)C>[CH:36]1([NH:35][C:34]([NH:33][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)=[O:8])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)O)cc1
Agent: COc1cc(O)cc(OC)c1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 2 h

Procedure:
For reaction by the active ester process, 14.6 g. (0.06 mol) N-(toluene-4-sulphonyl)-L-alanine and 12.2 g. (0.09 mol) N-hydroxybenzotriazole are dissolved in 300 ml. anhydrous ethyl acetate, cooled to 0° C. and mixed with 12.4 g. (0.06 mol) dicyclohexylcarbodiimide. For the formation of the active ester, the reaction mixture is stirred for 2 hours at 0° C. and then for a further 2 hours at ambient temperature. After the addition of 6.2 g. (0.04 mol) 3,5-dimethoxyphenol and 5.5 ml. (0.04 mol) triethylamine, the reaction mixture is stirred for 15 hours at ambient temperature. The N,N'-dicyclohexylurea formed is filtered off with suction and the filtrate is evaporated in a vacuum at a maximum bath temperature of 50° C. The residue is taken 200 ml. ethyl acetate and successively washed, in each case three times, with 100 ml. amounts of 5% citric acid and then with 100 ml. amounts of 5 % sodium bicarbonate solution. After drying with anhydrous sodium sulphate, the organic phase is evaporated in a vacuum. The oily crude product obtained is purified column chromatographically with a silica gel column, using tolueneethyl acetate (4:1 v/v) as elution agent. After evaporating the appropriately collected fractions, the residue is dissolved in a little methylene chloride and the product precipitated out by the addition of diethyl ether, there being obtained 5.8 g. (38% of theory) 1-[N-(toluene-4'-sulphonyl)-L-alanyloxy]3,5-dimethoxybenzene in the form of colorless crystals; m.p. 110° C.; αD20 : -52.5° (c=1% in acetone).
Reaction SMILES: [OH:1][CH:2]([CH:6]([NH:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[C:22]1[N:23]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[S:25][CH:26]=1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3](O)=[O:4].[CH:34]1([NH2:37])[CH2:36][CH2:35]1.ClCCl.CCN(C(C)C)C(C)C>>[CH:34]1([NH:37][C:3](=[O:4])[CH:2]([OH:1])[CH:6]([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][C:17]=2[C:22]2[N:23]=[C:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[S:25][CH:26]=2)[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:36][CH2:35]1
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-c1csc(-c2ccccc2)n1
Reactant: NC1CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC(Cc1ccccc1)C(O)C(=O)NC1CC1)c1cccnc1-c1csc(-c2ccccc2)n1
Temperature: 5 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a solution of 2-hydroxy-4-phenyl-3-(2-(2-phenylthiazol-4-yl)nicotinamido)butanoic acid (230 mg, 0.501 mmol) and cyclopropylamine (40 μL, 0.570 mmol) in dichloromethane (30 ml) 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate (HATU) (230 mg, 0.605 mmol) and DIPEA (100 μL, 0.605 mmol) were added at 5° C. The mixture was stirred for 1 hour at 5° C. and then for 5 hours at room temperature. The mixture was concentrated under reduced pressure, 40 ml of water added, the precipitate formed filtered off with suction, washed with water and dried in vacuo to give 227 mg of a white amorphous solid;
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][C:5]2[S:8][C:9]([C:11]([O-:13])=O)=[N:10][C:4]=2[CH2:3]1.[Li+].Cl.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH:32]([CH2:36][C:37]([N:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[O:38])[CH2:31]1)(=[O:29])=[O:28])[CH:21]=[CH:20]2>>[ClH:16].[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][N:33]([C:11]([C:9]3[S:8][C:5]4[CH2:6][NH:7][CH:2]([CH3:1])[CH2:3][C:4]=4[N:10]=3)=[O:13])[CH:32]([CH2:36][C:37]([N:39]3[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]3)=[O:38])[CH2:31]1)(=[O:29])=[O:28])[CH:21]=[CH:20]2
Reactant: O=C(CC1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1)N1CCCCC1
Reactant: CC1Cc2nc(C(=O)[O-])sc2CN1
Agent: Cl
Agent: [Li+]
Product: CC1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3CC(=O)N3CCCCC3)sc2CN1

Procedure:
Starting materials: lithium 6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate, 1-[(6-chloronaphthalen-2-yl)sulfonyl]-3-[[(piperidin-1-yl)carbonyl]methyl]piperazine hydrochloride
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[C:26]([OH:32])[CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1>[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[C:26]([O:32][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:25]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1
Product: COc1cc2nccc(Oc3cc(OCc4ccccc4)ccc3C=O)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h

Procedure:
4-Chloro-6,7-dimethoxyquinoline (111 mg), 4-benzyloxy-2-hydroxybenzaldehyde (456 mg), and 4-dimethylaminopyridine (244 mg) were suspended in monochlorobenzene (2 ml), and the suspension was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give 4-(benzyloxy)-2-[(6,7-dimethoxy-4-quinolyl)oxy]benzaldehyde.