Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])=O.[NH4+].[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH:21][C:22]([C:24]4([CH:36]([OH:38])[CH3:37])[CH2:28][CH2:27][N:26](CC5C=CC=CC=5)[CH2:25]4)=[O:23])[CH:19]=3)[N:14]([C:39]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:13]=2)=[CH:8][CH:7]=1>CO.[Pd]>[F:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH:21][C:22]([C:24]4([CH:36]([OH:38])[CH3:37])[CH2:28][CH2:27][NH:26][CH2:25]4)=[O:23])[CH:19]=3)[N:14]([C:39]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[N:13]=2)=[CH:10][CH:11]=1
Reactant: CC(O)C1(C(=O)Nc2ccc3c(c2)c(-c2ccc(F)cc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(O)C1(C(=O)Nc2ccc3c(c2)c(-c2ccc(F)cc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)CCNC1
Yield: 86.2 %

Procedure:
Added ammonium formate (100 mg, 1.58 mmol) to a suspension of 1-Benzyl-3-(1-hydroxy-ethyl)-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1-trityl-indazol-5-yl]-amide (5N) (80 mg, 0.114 mmol) and 10% Pd/C (5 mg) in MeOH (5 ml) at room temperature then refluxed for 4 hours. The reaction was cooled, diluted with MeOH (20 ml) and filtered through a celite pad. The filtrate was concentrated and the residue dissolved in MeCl2 (40 ml), dried over MgSO4, filtered and solvent evaporated yielding 6N as a solid (60 mg, 87%) ESMS (MH, 611).
Reaction SMILES: CC(C[AlH]CC(C)C)C.[OH:10][C:11]1[CH:12]=[CH:13][C:14]2[C:18]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:23][CH:22]=3)=[O:20])=[C:17]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3O)[S:16][C:15]=2[CH:44]=1>C1COCC1>[N:30]1([CH2:29][CH2:28][O:27][C:24]2[CH:23]=[CH:22][C:21]([CH:19]3[C:18]4[C:14]5[CH:13]=[CH:12][C:11]([OH:10])=[CH:44][C:15]=5[S:16][C:17]=4[CH2:36][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=4[O:20]3)=[CH:26][CH:25]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(Cc2ccccc2O)sc2cc(O)ccc12
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: Oc1ccc2c3c(sc2c1)Cc1ccccc1OC3c1ccc(OCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
Add DIBAL solution (5 mL, 1M/THF) dropwise to [6-hydroxy-2-(2-hydroxy-benzyl)-benzo[b]thiophen-3-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (300 mg, 0.6 mmol) in THF (5 mL) at −78° C. Stir for 30 min and quench with water, followed by TFA (5 mL). Stir the mixture for 3 h while warming to r.t. Remove the solvent in vacuo and dissolve the residue in i-PrOH/CH2Cl2 (1:3). Wash the organic phase with water and brine, dry over MgSO4, filter and concentrate. Purify by flash chromatography (0–5% (2M NH3 in MeOH)/CH2Cl2) to afford 5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,11-dihydro-6-oxa-12-thia-dibenzo[a,f]azulen-2-ol (180 mg, 62%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13](C(O)=O)[N:12]2[C:7](=[CH:8][O:9][C:10]3[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=32)[N:6]=1)=[O:4]>C(Cl)(Cl)Cl>[CH:13]1[N:12]2[C:7]([CH2:8][O:9][C:10]3[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=32)=[N:6][C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)C1=NC2=COc3ccccc3N2C1C(=O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cn2c(n1)COc1ccccc1-2
Yield: 83 %

Procedure:
20 g (0.073 mole) of the 4H-2-methoxycarbonyl-imidazo-[2,1-c][1,4]-benzoxazine-1-carboxylic acid obtained in Step D were added to a flask provided with a magnetic stirrer and the flask was placed in an oil bath at 175°-80° C. Stirring was continued for about twenty minutes until effervescence ceased and the decarboxylated product thus formed was then dissolved in chloroform and the solution obtained was passed down a short silica column to remove any remaining low Rf impurities. The combined fractions containing methyl 4H-imidazo-[2,1-c][1,4]-benzoxazine-2-carboxylate were then evaported to dryness and ether was added with trituration. The offwhite product was filtered off, washed with a little ether and dried to obtain 14.0g (83% yield) of methyl 4H-imidazo-[2,1-c][1,4]-benzoxazine-2-carboxylate with a melting point of 133°-4° C.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([O:15]C)[CH:10]1[O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])C1C=CC=CC=1>C(OCC)(=O)C.[H][H].[Pd]>[OH:15][CH:11]1[CH2:12][CH2:13][CH2:14][CH:9]([O:8][CH3:1])[CH:10]1[O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: [H][H]
Reactant: COC1CCCC(OCc2ccccc2)C1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC1CCCC(O)C1O[Si](C)(C)C(C)(C)C

Procedure:
A solution of racemic [1-benzyloxy-3-methoxy-2-cyclohexanoxy]tert-butyl-dimethylsilane, 51e, (3.4 g, 9.7 mmol) was dissolved in ethyl acetate (50 mL) and hydrogenated under 45 PSI of hydrogen with Pd—C 10% for 1 h. The reaction mixture was filtered over a nylon/fiberglass filter to provide, after concentration in vacuo 2.72 g of desired product 51f. This material was used directly in the next step without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:63][O:64][C:65]1[CH:71]=[C:70]([N:72]2[CH:76]=[N:75][N:74]=[N:73]2)[CH:69]=[CH:68][C:66]=1[NH2:67]>>[CH3:63][O:64][C:65]1[CH:71]=[C:70]([N:72]2[CH:76]=[N:75][N:74]=[N:73]2)[CH:69]=[CH:68][C:66]=1[NH:67][C:30]([CH:20]1[NH:19][CH:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C:17]2([C:12]3[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=3)[NH:15][C:16]2=[O:38])[CH:21]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[F:29])=[O:32]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COc1cc(-n2cnnn2)ccc1N
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-n2cnnn2)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F
Yield: 29.9 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.25 g, 0.43 mmol), was reacted with diisopropylethylamine (0.29 g, 2.2 mmol), diphenylphosphinic chloride (0.21 g, 0.89 mmol), then reacted with 2-methoxy-4-(1H-tetrazol-1-yl)aniline (Bionet) (0.13 g, 0.66 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (2-methoxy-4-tetrazol-1-yl-phenyl)-amide as a white solid (Yield 82 mg, 30%).
Reaction SMILES: CS(C)=O.CC(C)([O-])C.[K+].[NH2:11][C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1.Br[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=1>O>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)=[N:20][CH:21]=1)([O-:27])=[O:26]
Reactant: Nc1cncnc1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Nc2cncnc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To 7 ml of dimethyl sulfoxide was added 0.69 g (6.15 mmol) of potassium tert-butoxide, and 468 mg (4.92 mmol) of 5-aminopyrimidine was added to the solution while cooling with water. After stirring at room temperature for 1 hour, 500 mg (2.46 mmol) of 2-bromo-5-nitropyridine was added thereto under cooling with water, followed by further stirring at room temperature for 30 minutes. The reaction solution was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid, and the washing was adjusted to pH 8.5 with a 1 N sodium hydroxide aqueous solution and again extracted with ethyl acetate. The organic layer was combined with the above obtained organic layer, washed successively with water and a saturated sodium chloride aqueous solution, and dried over magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: chloroform-methanol). The resulting crude crystals were washed with ethyl ether to obtain 0.32 g (1.47 mmol) of 5-[N-(5-nitro-2-pyridyl)amino]pyrimidine.
Reaction SMILES: C[O:2][C:3]1[CH:22]=[CH:21][C:6]2[O:7][CH2:8][C:9]3[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=3[CH:11]([CH2:12][CH2:13][CH2:14][NH:15][CH3:16])[C:5]=2[CH:4]=1.I>C(O)(=O)C>[OH:2][C:3]1[CH:22]=[CH:21][C:6]2[O:7][CH2:8][C:9]3[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=3/[C:11](=[CH:12]/[CH2:13][CH2:14][NH:15][CH3:16])/[C:5]=2[CH:4]=1
Reactant: CNCCCC1c2ccccc2COc2ccc(OC)cc21
Agent: I
Solvent: CC(=O)O
Product: CNCC/C=C1/c2ccccc2COc2ccc(O)cc21
Temperature: 90 °C

Procedure:
A mixture of 2-methoxy-11-(3-methylaminopropyl)-6,11-dihydrodibenzo[b,e]oxepin (0.005 mol) with glacial acetic acid (0.2 ml) and hydriodic acid (0.2 ml, 57%) is stirred and heated for 5 hr at 90° C. The product is then extracted and purified by pouring into ice water (25 mL), made alkaline with sodium hydroxide (2N) and extracted with ether (2×10 mL). The aqueous layer is then adjusted to pH 6.8 with hydrochloric acid (6N). The mixture is then brought to pH 7 by the addition of sodium bicarbonate solution (5%) and extracted with chloroform (2×10 mL). The extract is dried over anhydrous sodium sulfate and evaporated in vacuo to give a yellowish solid. The crude reaction product is purified by preparative TLC (chloroform/toluene/methanol/ammonia, 4:3:2:1, v/v).
Reaction SMILES: Cl[O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:11]([C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16])=[CH2:12].C(N(C(C)C)C(C)C)C>CCOCC>[C:5]1([C:4]2[CH2:12][CH:11]([C:13]3[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=3[C:15]([O:17][CH3:18])=[O:16])[O:2][N:3]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: ClON=Cc1ccccc1
Reactant: C=Cc1ccccc1C(=O)OC
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccccc1C1CC(c2ccccc2)=NO1
Reaction time: 4 h
Yield: 79.5 %

Procedure:
To a stirred solution of 9.4 g (0.0604 mol) of benzaldehyde chlorooxime and 10.76 g (0.0664 mol) of methyl o-vinyl-benzoate in 100 ml of ether at 0°-5° C. was added dropwise a solution of 7.81 g (0.0604 mol) of ethyldiisopropylamine in 35 ml of ether during 30 minutes. The mixture was stirred in an ice bath for 4 hours, diluted with another 400 ml of ether, extracted three times with water, and concentrated under vacuum to a solid. This solid was washed with 200 ml of hexane. The undissolved solid product, 14.21 g, had mp 90°-94° C. Crystallization of this from 100 ml of methanol gave 13.50 g (79%) of white solid, mp 93.5°-95° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][O:15][CH3:16])[CH2:9]1)C1C=CC=CC=1.[ClH:17].O1CCOCC1>C(O)C.[C].[Pd]>[ClH:17].[CH3:16][O:15][CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: COC[C@@H]1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: COC[C@@H]1CNCCO1
Temperature: 40 °C
Reaction time: 6 h

Procedure:
(2S)-4-Benzyl-2-methoxymethylmorpholine (3 g) is dissolved in ethanol (50 ml) and thereto are added 4N hydrogen chloride/dioxane (3.4 ml) and 10% palladium-carbon (0.3 g), and the mixture is stirred under hydrogen pressure of 5 kg/cm2 at 40° C. for 6 hours. After removing palladium-carbon, the solvent is distilled off under reduced pressure. The residue is recrystallized from ethyl acetate-methanol to give the title compound (1.8 g).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([NH2:8])=[O:7].Cl[C:19]([S:21]Cl)=[O:20]>C1(C)C=CC=CC=1.CCCCCC.CO>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([C:6]2[O:7][C:19](=[O:20])[S:21][N:8]=2)[CH:9]=[C:10]([C:12]([F:15])([F:13])[F:14])[CH:11]=1
Reactant: O=C(Cl)SCl
Reactant: NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CO
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=c1oc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ns1
Reaction time: 12 h
Yield: 29.7 %

Procedure:
3,5-Bis(trifluoromethyl)benzamide (60.5 g, 0.235 mol) and five equivalents of chlorocarbonylsulfenyl chloride (154 g, 1.175 mol) were heated in 600 ml of toluene at reflux, with stirring, for 12 hours. The crude product, a dark brown oil, weighed 77.5 g. After decolorization in hexane, the material was taken up in methanol and recrystallized three times to give 22.0 g (0.0699 mol, 29.75%) of pale gold solid, m.p. 61°-62.5°.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[NH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:11]1([CH3:20])[C:12]([C:17](Cl)=[O:18])=[CH:13][CH:14]=[CH:15][CH:16]=1>N1C=CC=CC=1>[CH3:20][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:18]
Reactant: Nc1ccccc1
Reactant: Cc1ccccc1C(=O)Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: c1ccncc1
Product: Cc1ccccc1C(=O)Nc1ccccc1
Reaction time: 2 h

Procedure:
A three necked flack having a capacity of 100 ml, and equipped with a dropping funnel, a thermometer and a drying tube packed with calcium chloride, was charged with 11.2 g of aniline and 30 ml of pyridine. While stirring the solution in the flack by using a magnetic stirrer, 18.5 g of o-toluoyl chloride was added dropwise from the dropping funnel to the solution in such a manner that the temperature of the resultant reaction mixture did not exceed a level of 40° C. Simultaneously with the start of the dropwise addition, an exothermic reaction occurred, and a solid substance was gradually precipitated. Finally, the entire reaction system was solidified so that the stirring became impossible. The reactionwas completed after 2 hours from the start thereof. To the reaction system,an acid water containing hydrochloric acid was added, and then the solid product was pulverized and filtered to collect the reaction product. The reaction product was recrystallized by using a mixed solvent consisting ofethyl alcohol and water. White crystals were obtained in an amount of 24.1 g, and had a melting temperature of 127° C. to 129° C. An NMR measurement, a mass spectrometric analysis and an IR measurement identified that the resultant crystals consisted of the aimed compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:14]=1>>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:19]([C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)(=[O:21])=[O:20])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: Nc1ccc(Cl)c2cccnc12
Product: O=S(=O)(Nc1ccc(Cl)c2cccnc12)c1cccnc1
Yield: 42.4 %

Procedure:
In a similar fashion using route 14 general procedure 26, 5-chloroquinolin-8-amine (Intermediate 27) (50 mg, 0.28 mmol), pyridine-3-sulfonyl chloride (Intermediate 17) (74 mg, 0.42 mmol) gave the title compound (38 mg, 43%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].Br[CH2:11][C:12]1[CH:25]=[C:24]2[C:26]3=[C:27]4[C:17]([CH:18]=[CH:19][CH:20]=[C:21]4[CH:22]=[CH:23]2)=[CH:16][CH:15]=[C:14]3[CH:13]=1.[C:28](#[N:30])[CH3:29]>>[Cl-:1].[CH:13]1[C:14]2[C:26]3=[C:27]4[C:17](=[CH:16][CH:15]=2)[CH:18]=[CH:19][CH:20]=[C:21]4[CH:22]=[CH:23][C:24]3=[CH:25][C:12]=1[CH2:11][N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N:5]([CH2:29][C:28]2[CH:16]=[CH:15][C:14]3[C:13](=[CH:12][CH:25]=[CH:24][CH:26]=3)[N:30]=2)[CH:4]=1
Reactant: BrCc1cc2ccc3cccc4ccc(c1)c2c34
Reactant: CC#N
Reactant: Clc1nc[nH]c1Cl
Agent: [K+]
Agent: [OH-]
Product: Clc1c(Cl)[n+](Cc2cc3ccc4cccc5ccc(c2)c3c45)cn1Cc1ccc2ccccc2n1
Product: [Cl-]

Procedure:
4,5-Dichloroimidazole (0.18 g, 1.33 mmol) and potassium hydroxide (0.08 g, 1.46 mmol) will be dissolved in a minimum volume of acetonitrile and stirred at reflux for 30 min. 2-(Bromomethyl)pyrene (2.95 g, 10.0 mmol) will be added and the mixture will be returned to reflux for 3 h. The mixture will be filtered hot to remove the KBr generated. A solution of 2-(chloromethyl)quinoline will be prepared by combining 2-(chloromethyl)quinolone hydrochloride (2.14 g, 10 mmol) and potassium hydroxide (0.56 g, 10.0 mmol) in acetonitrile and refluxing the mixture for 30 min, and this solution will be added to the filtrate. The combined mixture will be returned to reflux for 6 h. The volatile components will be removed under reduced pressure, and the resulting solid will be washed with water to remove the KCl generated in the neutralization of the quinoline. The remaining solid will be dried and will be the product.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH:5]([C:6]([O:8]CC)=O)[C:4]1([CH2:20][CH3:21])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1.C(=O)([O-])O.[Na+].C[N:28]([CH3:31])C=O>>[CH2:20]([C:4]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[CH:5]2[CH:3]1[CH2:2][N:28]([CH2:31][CH2:3][CH2:4][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]2=[O:8])[CH3:21]
Reactant: CN(C)C=O
Reactant: CCOC(=O)C1C(CCl)C1(CC)c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCC1(c2cccc([N+](=O)[O-])c2)C2CN(CCCc3ccccc3)C(=O)C21
Temperature: 150 °C

Procedure:
To a solution of ethyl 3-(chloromethyl)-2-ethyl-2-(3-nitrophenyl)cyclopropane carboxylate (Preparation 16, 3.5 g, 11.2 mmol), in N,N-dimethylformamide (33 ml) was added sodium hydrogen carbonate (3.3 g, 39 mmol) and 3-phenylpropylamnine (10.6 g, 11.2 ml, 79.2 mmol). The mixture was heated to 150° C. for 12 h, then cooled to room temperature and partitioned between water (500 ml) and diethyl ether (500 ml). The organic layer was washed successively with water (4×250 ml). The aqueous layers were combined and extracted with diethyl ether (250 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica (200 g) column chromatography eluting with dichloromethane. Product-containing fractions were combined and concentrated in vacuo to give the title compound as a very pale yellow oil (1.8 g, 43%).
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=1)=O.Cl.[C:14]([O:18][C:19](=[O:23])[C@@H:20]([CH3:22])[NH2:21])([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C.[BH4-].[Na+]>CO.C(Cl)Cl>[C:11]([C:8]1[CH:9]=[CH:10][C:5]([CH:3]([NH:21][C@@H:20]([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:23])[CH3:22])[CH2:2][OH:1])=[CH:6][CH:7]=1)#[N:12]
Reactant: N#Cc1ccc(C(=O)CO)cc1
Reactant: C[C@@H](N)C(=O)OC(C)(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](NC(CO)c1ccc(C#N)cc1)C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 1 h
Yield: 43.5 %

Procedure:
To a solution of 2-Hydroxy-1-(4-cyanophenyl)ethanone (3.2 g, 0.0198 mol) in methanol and DCM (1:1) (100 ml) were added D-Alanine t-butyl ester hydrochloride (3.6 g, 0.0198 mol) and triethylamine (6.9 ml, 0.0495 mol) at RT. The reaction mixture was heated at 70° C. for 18 h. The reaction mixture was cooled to 0° C. and NaBH4 (0.9 g, 0.0237 mol) was added in portions and stirred at RT for 1 h. The reaction mixture was quenched with ice, extracted with DCM (2×100 ml), dried over sodium sulphate and evaporated. The crude material was purified by column chromatography using chloroform and methanol (90:10) as an eluent to afford (2.5 g, 43%) of title compound as brown oil. 1H NMR: (CD3OD, 400 MHz) δ 7.71-7.69 (d, J=8.36 Hz, 2H), 7.59-7.56 (d, J=8.08 Hz, 2H), 4.76-4.74 (t, J=6.32 Hz, 1H), 3.64-3.61 (q, 2H), 3.44-3.42 (d, J=7.04 Hz, 1H), 1.47 (s, 9H), 1.30-1.28 (d, J=7.04 Hz, 3H). LC/MS (Method A): 291.3 (M+H)+. HPLC (Method A) Rt 2.95 min. (Purity: 76.8%).
Reaction SMILES: [F:1][C:2]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]=[C:13]=[O:14].Cl.Cl.[CH2:22]([O:29][C:30](=[O:38])[CH2:31][C@@H:32]([NH2:37])[CH2:33][N:34]([CH3:36])[CH3:35])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl>[CH2:22]([O:29][C:30](=[O:38])[CH2:31][C@@H:32]([NH:37][C:13]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][C:3]1[CH:15]=[CH:16][CH:17]=[C:18]([F:19])[C:2]=1[F:1])=[O:14])[CH2:33][N:34]([CH3:35])[CH3:36])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C=NCCCCCCOCc1cccc(F)c1F
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)NCCCCCCOCc1cccc(F)c1F
Reaction time: 1 h
Yield: 13.3 %

Procedure:
A solution of [6-(2,3-difluoro-benzyloxy)-hexyl]-isocyanate (224 mg, 0.83 mmol) in dichloromethane (1 mL) was added at 0° C. to a suspension of (R)-3-amino-4-dimethylamino butyric acid benzyl ester dihydrochloride (255 mg, 0.83 mmol) in dichloromethane (4 mL), then a solution of triethylamine (167 mg, 1.65 mmol) in dichloromethane (1 mL) was added dropwise over 25 min. The reaction mixture was kept at <5° C. for 1 h, then allowed to reach room temperature over 1 h. Insoluble material was removed by filtration and the filtrate evaporated. The residue was purified by preparative HPLC to afford (R)-3-{3-[6-(2,3-difluoro-benzyloxy)-hexyl]-ureido}-4-dimethylamino-butyric acid benzyl ester (56 mg, 13%) as a colorless oil.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[C:17]([C:21](=O)[NH2:22])=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=O)(C)(C)C.P(Cl)(Cl)([Cl:26])=O>C(N(CC)C=O)C>[ClH:26].[NH2:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[C:17]([C:21]#[N:22])=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)NCCOc1noc2cccc(C(N)=O)c12
Agent: CCN(C=O)CC
Product: Cl
Product: N#Cc1cccc2onc(OCCN)c12
Temperature: 5 °C
Yield: 116.2 %

Procedure:
To a solution of 3-(2-(N-t-butoxycarbonylamino)ethoxy)-4-carbamoyl-1,2-benzisoxazole (0.15 g) in diethylformamide (1.5 ml) was added phosphorus oxychloride (0.09 g) with stirring at 5° C., and the mixture was then stirred at the same temperature for 15 minutes. The reaction mixture was poured into ice water (20 ml), extracted with ethyl acetate (twice each with 20 ml) and the combined extracts were dried over anhydrous magnesium sulphate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography with cyclohexane/ethyl acetate (4/1) as an eluent, to give the title compound (0.13 g, 93%) as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:26])[CH2:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[CH3:12][O:13][C:14](=[O:26])[CH2:15][N:16]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccc(O)cc1
Reactant: COC(=O)CNCc1ccc(OC)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CN(Cc1ccc(OC)cc1)S(=O)(=O)c1ccc(O)cc1

Procedure:
To a solution of 8.7 g (45.2 mmol) of 4-hydroxybenzenesulfonyl chloride in 80 ml of CH2Cl2, a solution of 6.75 g (32.3 mmol) of (4-methoxy-benzylamino)-acetic acid methyl ester in 20 ml of CH2Cl2 and 12 ml (79.2 mmol) of triethylamine were added dropwise at 0° C. The resulting mixture is stirred for 4 h at r.t., neutralized with cold 1 N aqueous HCl and extracted with CH2Cl2. The combined extracts are washed with H2O and brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent; AcOEt:CH2Cl2=50:1˜5:1) to give [(4-hydroxy-benzenesulfonyl)-(4-methoxy-benzyl)-amino]-acetic acid methyl ester; NMR (CDCl3): 3.57 (s, 3H), 3.79 (s, 3H), 3.90 (s, 2H), 4.40 (s, 2H), 5.59 (s, 1H), 6.84 (d, 2H, J=8.6 Hz), 6.93 (d, 2H, J=10.64 Hz), 7.15 (d, 2H, J=8.6 Hz), 7.82 (d, 2H, J=10.64 Hz).