Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:33]3[N:34]=[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][N:36]4[CH:41]=3)[CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:33]3[N:34]=[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][N:36]4[CH:41]=3)[CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2ccc(-c3cn4ccccc4n3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc2ccc(-c3cn4ccccc4n3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-propyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][N:10]2[Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])=[O:4].[CH3:31][NH2:32]>>[CH3:31][NH:32][CH2:2][C:3]([N:5]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][N:10]2[Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])=[O:4]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(N(C(=O)CCl)c3ccccc3)cccc21
Reactant: CN
Product: CNCC(=O)N(c1ccccc1)c1cccc2c1ccn2[Si](C(C)C)(C(C)C)C(C)C

Procedure:
A solution of 2-chloro-N-phenyl-N-(1-triisopropylsilanyl-1H-indol-4-yl)-acetamide XXII (192 mg, 0.435 mmol) and MeNH2 (33% w in EtOH, 2 ml) was stirred for 2.5 h. The solvent was evaporated and the residue was partitioned between EtOAc and a saturated solution of NaHCO3. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated, and the resulting crude 2-methylamino-N-phenyl-N-(1-triisopropylsilanyl-1H-indol-4-yl)-acetamide XXIII (180 mg) was used without further purification for the next reaction.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].Cl.[CH3:9][NH:10][O:11][CH3:12].N1C=CC=CC=1>C(Cl)Cl.CCOCC>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([N:10]([CH3:9])[O:11][CH3:12])=[O:6]
Reactant: O=C(Cl)CCCCl
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CON(C)C(=O)CCCCl
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
To a solution of 4-chlorobutanoyl chloride (5.64 g, 40.0 mmol) and a N,O-dimethylhydroxylamine hydrochloride (3.91 g, 40.0 mmol) in CH2Cl2 (80 mL) at 0° C., was added pyridine (7.2 ml, 88.0 mmol) in CH2Cl2 (30 mL). This mixture was kept stirring at 0° C. for 1 h, then warmed to rt. The reaction mixture then diluted with Et2O (200 mL), washed with saturated 1N HCl (2×), saturated NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated to afford the title compound as a colorless oil (6.28 g, 95%). MS (ES+) m/e 166 [M+H]+.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:6]([CH2:7][CH2:8][O:9]S(C2C(C)=CC=CC=2)(=O)=O)[NH:5][C:4]1=[O:20])[CH3:2].[C:21]1([SH:27])[CH:26]=[CH:25][CH:24]=CC=1.[K]>C(O)C>[CH2:1]([C@H:3]1[C@@H:6]([CH2:7][CH2:8][O:9][C:24]2[S:27][CH:21]=[CH:26][CH:25]=2)[NH:5][C:4]1=[O:20])[CH3:2]
Reactant: CC[C@@H]1C(=O)N[C@@H]1CCOS(=O)(=O)c1ccccc1C
Reactant: Sc1ccccc1
Agent: [K]
Solvent: CCO
Product: CC[C@@H]1C(=O)N[C@@H]1CCOc1cccs1

Procedure:
To 8 mg of the titled product of Example 10 Step C in 1 ml of absolute ethanol was added a small amount of potassium thiophenol. The resulting mixture was refluxed for 1/2 hour and the product purified by preparative TLC (30% EtOAc in hexane). 1H NMR (CDCl3): δ1.04(3H, t), 1.46-1.98(4H, m), 2.97(2H, t), 3.06-3.16(1H, m), 3.77-3.85(1H, m), 5.99 (1H, broad), 7.16-7.36(5H, m).
Reaction SMILES: O.[I-].[I:3][C:4]1[CH:5]=[C+:6][C:7]2[NH:8][C:9]3[C:14]([Se:15][C:16]=2[CH:17]=1)=[CH:13][C:12](I)=[CH:11][CH:10]=3.[I-].C(N([C:27]1[CH:28]=[CH:29][C:30]2[NH:31][C:32]3[C:37]([SeH+][C:39]=2[CH:40]=1)=[CH:36][C:35](N(CCC)CCC)=[CH:34][CH:33]=3)CCC)CC.C(N(CC)CC)C.[CH2:55]([NH:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])[CH2:56][CH2:57][CH2:58][CH2:59][CH3:60]>CO>[I-:3].[CH2:62]([N:61]([C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([SeH+:15][C:16]=2[CH:17]=1)=[CH:13][C:12]([N:31]([CH2:30][CH2:29][CH2:28][CH2:27][CH2:40][CH3:39])[CH2:32][CH2:37][CH2:36][CH2:35][CH2:34][CH3:33])=[CH:11][CH:10]=3)[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])[CH2:63][CH2:64][CH2:65][CH2:66][CH3:67]
Reactant: IC1=CC2=C([C+]=C1)Nc1ccc(I)cc1[Se]2
Reactant: CCCN(CCC)c1ccc2c(c1)[SeH+]c1cc(N(CCC)CCC)ccc1N2
Reactant: CCCCCCNCCCCCC
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: CCCCCCN(CCCCCC)c1ccc2c(c1)[SeH+]c1cc(N(CCCCCC)CCCCCC)ccc1N2
Reaction time: 24 h
Yield: 21 %

Procedure:
To a solution of 3,7-diiodo-phenoselenazin-ylium iodide hydrate (2.34 g) (prepared as above for Compound 2) in methanol (300 cm3) was added triethylamine (1.0 cm3) followed by dihexylamine (5 cm3). The reaction was stirred for 24 hours. The residue remaining after removal of the methanol was taken up in dichloromethane and washed with dilute hydriodic acid (5% w/w) followed by water. The organic phase was isolated and dried (MgSO4). Flash column chromatography over silica gel 60 Å was performed on the crude material using a mobile phase of 85/15 methanol/water containing 3% w/v ammonium acetate. After isolation of the desired fractions and removal of the methanol, the product was extracted from the aqueous phase using dichloromethane. Concentration of the dichloromethane in vacuo and addition of an excess of diethyl ether resulted in precipitation of the product. The product was collected by filtration, washed with diethyl ether and dried to give 3,7-bis-(N,N-dihexylamino)-phenoselenazin-5-ylium iodide as a dark coloured powder, in 21% yield.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(Cl)Cl>[Si:20]([O:19][CH2:18][CH2:17][N:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: C1CCCNCCC1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCN1CCCCCCC1
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of azocane (5.59 g, 49.4 mmol) and triethylamine (6.53 g, 64.7 mmol) in DCM (50 mL) at room temperature was added (2-bromoethoxy)(tert-butyl)dimethylsilane (13.0 g, 54.4 mmol). The mixture was stirred overnight, and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate, washed (brine (2×)), dried over Na2SO4 and filtered. The solvent was removed under reduced pressure, and the residue was purified on a silica gel column (eluting with PE/EA=10/1) to afford 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)azocane (11.8 g, 88%). LCMS: 272 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:17](Br)[O:16][C:12]=2[N:13]=[CH:14][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:17]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:16][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)CCCCCNc1ncnc2oc(Br)c(-c3ccccc3)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)CCCCCNc1ncnc2oc(-c3ccccc3)c(-c3ccccc3)c12

Procedure:
Stir 55 mg (0.131 mmol) 6-[(6-bromo-5-phenylfuro[2,3-d]pyrimidin-4-yl)amino]hexanoic acid methyl ester, 0.131 ml of 2 M aqueous sodium carbonate solution (0.26 mmol), 4.6 mg (0.006 mmol) bis(triphenylphosphine)palladium(II) chloride and 20 mg (0.164 mmol) phenylboronic acid under argon in 0.4 ml DMSO for 1 h at 80° C. After cooling, purify the mixture directly by preparative RP-HPLC (gradient: water/acetonitrile). 35 mg (64.1% of theor.) of the target compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[N:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:13]=[O:14]>C1COCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH:9][C:13]([NH:12][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:14])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN=C=O
Reactant: NNC(=O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)NNC(=O)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A suspension of 12.95 g (75.9 mmol) of 4-chlorobenzohydrazide in 50 ml of dry THF was initially charged at 50° C., and a solution of 10.0 g (77.5 mmol) of ethyl 2-isocyanatoacetate in 100 ml of dry THF was added dropwise. Initially, a solution was formed, and then a precipitate. After the addition had ended, the mixture was stirred at 50° C. for a further 2 h and then allowed to stand at RT overnight. The crystals were isolated by filtration, washed with a little diethyl ether and dried under high vacuum. This gave 21.43 g (89% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:8][CH:9]=[N:10][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:28]([C:30]1[CH:31]=[C:32]([S:37](Cl)(=[O:39])=[O:38])[CH:33]=[CH:34][C:35]=1[F:36])#[N:29]>CC1CCCO1.O1CCCC1.C(OCC)(=O)C>[C:28]([C:30]1[CH:31]=[C:32]([S:37]([N:6]([CH2:5][C:4]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=2[O:2][CH3:1])[C:7]2[S:8][CH:9]=[N:10][N:11]=2)(=[O:39])=[O:38])[CH:33]=[CH:34][C:35]=1[F:36])#[N:29]
Reactant: COc1ccc(CNc2nncs2)c(OC)c1
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC1CCCO1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Temperature: -50 °C
Reaction time: 0.08 h
Yield: 29.9 %

Procedure:
N-(2,4-Dimethoxybenzyl)-1,3,4-thiadiazol-2-amine (Preparation 14, 5.72 g, 22.8 mmol) was dissolved in 2-methyltetrahydrofuran (100 mL) and the suspension cooled to −50° C. A 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (34.1 mL, 34.1 mmol) was added slowly over 15 minutes. This suspension was stirred at −50° C. for 5 minutes, warmed to 10° C. then cooled again to −78° C. A solution of 3-cyano-4-fluorobenzene-1-sulfonyl chloride (10 g, 45.5 mmol) in tetrahydrofuran (20 mL) was then added drop wise. The pale orange solution was allowed to warmed to 20° C. for 18 hours. The reaction was quenched with an aqueous solution of saturated ammonium chloride (50 mL) and stirred vigorously for 5 minutes. Ethyl acetate (100 mL) was added and the layers separated. The organic layer was washed with water (100 mL) and concentrated in vacuo to give an orange gum. The gum was dissolved in ethyl acetate and eluted through a silica plug before being purified by silica gel column chromatography (ISCO™, 50% ethyl acetate in heptane) to afford the title compound as a pale yellow oil (2.96 g).
Reaction SMILES: [H][H].O[C:4]([C:11]1(OC)[CH:20]=[CH:19][C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:12]1)([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:23]([OH:25])C>[Pd]>[CH3:23][O:25][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([CH:4]([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:20]=[CH:19]2
Reactant: CCO
Reactant: [H][H]
Reactant: CCOC(=O)C(C)(O)C1(OC)C=Cc2ccccc2C1
Agent: [Pd]
Product: CCOC(=O)C(C)c1ccc2cc(OC)ccc2c1
Temperature: 160 °C
Reaction time: 6 h

Procedure:
Ethanol (48 g) and palladium catalyst (5% palladium on carbon, 0,12 g) were stirred under a hydrogen atmosphere (10 bar) for 1 hour. The hydrogen was released and ethyl 2-hydroxy-2-(6-methoxynaphth-6-yl)propionate (12,0 g, 43,8 mmol) was added. Hydrogen was charged to the reactor and the vessel was warmed to 160° C. (hydrogen pressure 20 bar). The reactor was stirred at 160° C. for 6 hours and the hydrogen was released. Ethyl 2-(6-methoxynaphth-2-yl)propionate was formed with a selectivity of 35% at 40% conversion of the starting material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].C(N(C(C)C)CC)(C)C.ClC(Cl)(O[C:37](=[O:43])OC(Cl)(Cl)Cl)Cl.[NH2:45][C:46]1[S:47][C:48]([CH2:51][CH3:52])=[N:49][N:50]=1>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:37]([NH:45][C:46]2[S:47][C:48]([CH2:51][CH3:52])=[N:49][N:50]=2)=[O:43])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Reactant: CCc1nnc(N)s1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nnc(NC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.7 %

Procedure:
3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (100 mg) was dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (100 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 15 min. Next, 2-amino-5-ethyl-1,3,4-thiadiazole (41 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Distilled water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine and was dried over sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by HPLC using chloroform/acetone for development to give 48 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(O)(=O)C.[CH:21](N)=[NH:22]>C(O)C>[N:11]1([C:9]2[CH:10]=[C:2]3[C:3]([C:4](=[O:6])[NH:22][CH:21]=[N:1]3)=[CH:7][CH:8]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: N=CN
Reactant: Nc1cc(N2CCOCC2)ccc1C(=O)O
Solvent: CCO
Solvent: CC(=O)O
Product: O=c1[nH]cnc2cc(N3CCOCC3)ccc12
Yield: 50.1 %

Procedure:
4.22 g (0.019 mol) of 2-amino-4-morpholin-4-ylbenzoic acid and 4.0 g (0.038 mol) of formamidine acetate were suspended in 40 ml of ethanol. The reaction mixture was subsequently stirred under reflux for 16 h. Conventional work-up gave 2.2 g (Y=50%) of 7-morpholin-4-yl-3H-quinazolin-4-one.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](S(OC[C@@H](O)C)(=O)=O)=[CH:4][CH:3]=1.[OH-].[K+].[CH2:18]([NH:25][CH2:26][CH2:27][OH:28])[C:19]1C=CC=C[CH:20]=1.CC([O:33]C(OC(OC(C)(C)C)=O)=O)(C)C>CCO>[CH2:1]([N:25]([CH2:26][CH2:27][OH:28])[CH2:18][C@H:19]([OH:33])[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](C)O)cc1
Reactant: OCCNCc1ccccc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C[C@@H](O)CN(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (2S)-2-hydroxypropyl 4-methylbenzenesulfonate (540 g, 2.34 mol) in EtOH (3 L) at 0° C. was added a solution of KOH (160 g, 2.5 mol) in ethanol (2 L). The mixture was maintained at room temperature overnight. Upon completion, 2-benzylamino-ethanol (500 g, 3.3 mol) was added to the reaction, and the resulting mixture was stirred at room temperature for two days. Boc2O (500 g, 2.29 mol) was then added and the mixture was stirred for another day. The mixture was then filtered, the filter cake washed with ethanol (500 mL), and the filtrate concentrated in vacuo. The residue was dissolved in EtOAc (3.5 L), washed with water (500 mL) and brine (500 mL), and concentrated in vacuo. The resulting crude residue was purified by silica gel chromatography (1:2 EtOAc:petroleum ether) to afford the title compound as a brown oil.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:33])[C:6]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]4[C:18]([C:21]([CH3:30])([O:23]C5CCCCO5)[CH3:22])=[N:19][N:20]=[C:14]4[CH:13]=3)[C:9]([CH3:31])=[C:8]([F:32])[CH:7]=2)[CH2:3][CH2:2]1.O.CC1C=CC(S(O)(=O)=O)=CC=1>CO.C(OCC)(=O)C>[CH:1]1([NH:4][C:5](=[O:33])[C:6]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]4[C:18]([C:21]([OH:23])([CH3:30])[CH3:22])=[N:19][N:20]=[C:14]4[CH:13]=3)[C:9]([CH3:31])=[C:8]([F:32])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccn2c(C(C)(C)OC3CCCCO3)nnc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccn2c(C(C)(C)O)nnc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
To a solution of N-cyclopropyl-3-fluoro-4-methyl-5-{3-[1-methyl-1-(tetrahydro-2H-pyran-2-yloxy)ethyl][1,2,4]triazolo[4,3-a]pyridin-7-yl}benzamide (0.065 g, 0.14 mmol) in methanol (1 mL) was added 4-methylbenzenesulfonic acid hydrate (0.010 mg, 0.06 mmol). The reaction mixture was stirred at room temperature for 5 hours, the solvent was concentrated under reduced pressure and the oil obtained was dissolved in ethyl acetate. The organic layer was washed with an aqueous solution of sodium bicarbonate and brine, dried over anhydrous sodium sulphate and concentrated. The crude was treated with diethyl ether to obtain the title compound (78%) as a solid.
Reaction SMILES: [CH2:1]([C@H:3]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][C:5]=2[O:4]1)[CH3:2].[H-].[Na+].I[CH:21]([CH3:23])[CH3:22].O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C@H:3]1[C:8](=[O:9])[N:7]([CH:21]([CH3:23])[CH3:22])[C:6]2[CH:10]=[CH:11][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][C:5]=2[O:4]1)[CH3:2]
Reactant: CC[C@@H]1Oc2cc(C(=O)OC)ccc2NC1=O
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@@H]1Oc2cc(C(=O)OC)ccc2N(C(C)C)C1=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
A solution of (S)-2-ethyl-7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (1.60 g) in dimethylformamide (50 ml) were added 60% sodium hydride (in oil) (0.27 g) and 2-iodopropane (1.38 g) and the mixture was stirred at 60° C. overnight. Water was added to the reaction solution and extraction with ethyl acetate was conducted. The solvent was distilled off under reduced pressure and the resulting residue was subjected to purification by column chromatography using ethyl acetate/hexane [1:4 (v/v) ] to give (S)-2-ethyl-7-methoxycarbonyl-4-(2-propyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (0.85 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH2:11])[CH2:7][CH2:6]1)=[O:4].CCN(CC)CC.[Cl:19][C:20]1[CH:21]=[N:22][C:23]([CH3:29])=[C:24]([CH:28]=1)[C:25](Cl)=[O:26]>C1COCC1>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:25]([C:24]2[C:23]([CH3:29])=[N:22][CH:21]=[C:20]([Cl:19])[CH:28]=2)=[O:26])[CH2:7][CH2:6]1)=[O:4]
Reactant: Cc1ncc(Cl)cc1C(=O)Cl
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](NC(=O)c2cc(Cl)cnc2C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trans-4-Amino-cyclohexanecarboxylic acid methyl ester (2.14 g, 11.05 mmol) is suspended in THF (50 mL) and Et3N (2.79 g, 27.6 mmol) and cooled to 0° C. 5-chloro-2-methylnicotinoyl chloride (step 1) (2.20 g, 11.05 mmol) is slowly added portionwise and the RM is stirred at r.t. for 2 hours. LCMS showed mainly product. The reaction mixture is partitioned between EtOAc and 1M HCl. The organic phase is washed with water and brine, dried over MgSO4, filtered and the solvent is removed in vacuo to afford the title product which is used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (1H, d), 7.42 (1H, 5), 7.80 (1H, d), 3.70 (1H, m), 3.60 (3H, s), 2.49 (3H, s), 2.29 (1H, m), 1.95 (4H, m), 1.42 (2H, m), 1.29 (2H, m); [MH]+311.26.
Reaction SMILES: [CH3:1][C:2]1([C:5]([OH:7])=[O:6])[CH2:4][CH2:3]1.S(Cl)(Cl)=O.[CH2:12](S)[CH3:13]>C(OCC)C>[CH2:12]([O:6][C:5]([C:2]1([CH3:1])[CH2:4][CH2:3]1)=[O:7])[CH3:13]
Reactant: CCS
Reactant: CC1(C(=O)O)CC1
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)C1(C)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
100 g of 1-methylcyclopropanoic acid was added to 150 ml of diethyl ether. The system was cooled to 0°-5° C. and 119 gm of thionyl chloride was added dropwise over a period of time. After addition, the system was heated at reflux for 8 hours. The system was then cooled to 0°-5° C. and 62 gm of ethanethiol was added dropwise. The system was heated at reflux for 6 hours and then stirred at room temperature for 72 hours. The diethyl ether was removed by stripping to give the 1-methylcyclopropanoic acid ethyl ester.
Reaction SMILES: C[C:2]([O:5][C:6]([C@@H:8]([NH:14]C(OCC1C=CC=CC=1)=O)[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])C.C1CCC(NC2CCCCC2)CC1.C1[O:40][CH:39]1CO.C(Cl)CCl.C(Cl)CCl.CN(C1C=CN=CC=1)C>ClCCl.CN(C1C=CN=CC=1)C>[CH2:2]([O:5][C:6](=[O:7])[C@H:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[NH2:14])[CH:4]1[O:40][CH2:39]1
Reactant: OCC1CO1
Reactant: CC(C)(C)OC(=O)[C@H](CCC(=O)O)NC(=O)OCc1ccccc1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: N[C@@H](CCC(=O)O)C(=O)OCC1CO1
Yield: 141.4 %

Procedure:
A solution of 1720 mg (3.38 mmol) of Z-Glu-OtBu DCHA in 17 mL of dichloromethane was cooled to 0° C. and treated with 0.448 mL (6.75 mmol, 2.0 equiv) of glycidol, 41.2 mg (0.338 mmol, 0.1 equiv) of DMAP and 970 mg (5.06 mmol, 1.5 equiv) of EDC according to the general procedure for EDC/DMAP esterification. Purification by flash chromatography (30×150 mm silica gel, 35% ethyl acetate/hexane) gave 971 mg (73%) of the title compound: 1H NMR (300 MHz, CD3OD) δ7.38-7.24 (m, 5H), 5.09 (s, 2H), 4.41 (dd, J=2.9, 12.4 Hz, 1H), 4.13-4.09 (overlapping dd, 1H), 3.91-3.84 (overlapping dd, 1H), 3.32-3.16 (m, 1H), 2.80-2.78 (overlapping t, 1H), 2.64-2.61 (overlapping dd, 1H), 2.47 (t, J=7.6 Hz, 2H), 2.20-2.08 (m, 1H), 1.97-1.84 (m, 1H), 1.45 (s, 9H); MS(FAB) 394 (M+1), 338, 294, 260.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[OH:16][N:17]1C(=O)CCC1=O.[CH2:24]([O:26][CH:27]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][S:48]([CH3:51])(=[O:50])=[O:49])=[CH:43][CH:42]=2)=[CH:34][CH:33]=1)[C:28]([OH:30])=O)[CH3:25].C(N(C(C)C)CC)(C)C.[CH2:61](NO)[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1.Cl>C(#N)C.CCCCCCC>[CH2:61]([O:16][NH:17][C:28](=[O:30])[CH:27]([O:26][CH2:24][CH3:25])[CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][S:48]([CH3:51])(=[O:49])=[O:50])=[CH:43][CH:42]=2)=[CH:36][CH:37]=1)[C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1
Reactant: ONCc1ccccc1
Reactant: CCOC(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCCC
Solvent: CC#N
Product: CCOC(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)NOCc1ccccc1
Yield: 65.5 %

Procedure:
DCC (1 g; 4.85 mmole) and N-hydroxy-succinimide acid (0.56 g; 4.85 mmole) were added to a solution of 2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic acid (described in Example 2) (1.65 g; 4.04 mmole) in acetonitrile (25 ml) at 0° C. After 1 hour a precipitate was filtered off and diisopropylethylamine (1.82 g; 14.1 mmole) and benzyl hydroxylamine (1.24 g; 8.08 mmole) dissolved in acetonitrile were added. After stirring overnight hydrochloric acid (2M) was added and the mixture was extracted with diethyl ether. The organic phase was washed with sodium carbonate solution and dried (magnesium sulfate). The solvent was removed and the crude product was purified by chromatography on silica gel using ethyl acetate:heptane (gradient 10-100% ethyl acetate) as eluant to give 1.36 g (yield 66%) of N-benzyloxy-2-ethoxy-3-[4-(2-{4-methanesulfonyloxy-phenyl}ethoxy)phenyl]propanoic amide.