Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:28]=1B(O)O.C(=O)([O-])O.[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:28]2[C:29]([O:33][CH3:34])=[CH:30][CH:31]=[CH:32][C:27]=2[F:26])[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: COc1cccc(F)c1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cccc(F)c1-c1cc(CN(C)C(=O)OC(C)(C)C)cn1S(=O)(=O)c1cccnc1
Temperature: 100 °C
Reaction time: 20 h
Yield: 21 %

Procedure:
tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (431 mg), (2-fluoro-6-methoxyphenyl)boronic acid (256 mg), sodium hydrogencarbonate (253 mg) and tetrakis(triphenylphosphine)palladium (176 mg) were added to a mixture of 1,2-dimethoxyethane (8 mL) and water (2 mL), and the mixture was stirred under a nitrogen atmosphere at 100° C. for 20 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as a colorless oil (yield 100 mg, 21%).
Reaction SMILES: C(OC([NH:11][CH2:12][C:13]1([CH3:36])[CH2:18][CH2:17][N:16]([C:19](=[O:35])[C@:20]([C@@H:28]2[CH2:32][CH2:31][C:30]([F:34])([F:33])[CH2:29]2)([OH:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]1)=O)C1C=CC=CC=1>CO.[C].[Pd]>[NH2:11][CH2:12][C:13]1([CH3:36])[CH2:18][CH2:17][N:16]([C:19](=[O:35])[C@:20]([C@@H:28]2[CH2:32][CH2:31][C:30]([F:33])([F:34])[CH2:29]2)([OH:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:15][CH2:14]1
Reactant: CC1(CNC(=O)OCc2ccccc2)CCN(C(=O)[C@](O)(c2ccccc2)[C@@H]2CCC(F)(F)C2)CC1
Agent: [Pd]
Solvent: CO
Product: CC1(CN)CCN(C(=O)[C@](O)(c2ccccc2)[C@@H]2CCC(F)(F)C2)CC1
Reaction time: 4 h
Yield: 29.9 %

Procedure:
To a solution of 16 mg of 4-benzyloxycarbonylaminomethyl-1-{(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylacetyl}-4-methylpiperidine in 2 ml of methanol, 4 mg of 10% palladium-carbon catalyst was added, followed by stirring,for 4 hours under a hydrogen atmosphere. After filtering the catalyst off, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 1M hydrochloric acid and washed with diethyl ether. After basifying with 3N sodium hydroxide, the aqueous layer was extracted with chloroform. The organic layer was then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 3.5 mg of the title compound as a colorless oily substance.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH:9]=[C:8]([Cl:12])[NH:7][C:6]1=[O:13])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1>CN(C)C=O>[CH2:1]([N:5]1[C:10](=[O:11])[CH:9]=[C:8]([Cl:12])[N:7]([CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[C:6]1=[O:13])[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(CCl)cc1
Reactant: CCCCn1c(=O)cc(Cl)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCn1c(=O)cc(Cl)n(Cc2ccc(OC)cc2)c1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 3-butyl-6-chlorouracil (5.0 g, 24.6 mM), potassium carbonate (4.4 g, 32 mM) and potassium iodide (0.17 g, 1 mM) in dimethylformamide [DMF] (50 ml) was added 4-methoxybenzyl chloride (4.65 ml, 32 mM). The mixture was stirred at room temperature for 5 hours and was then concentrated under reduced pressure, and the resulting residue was diluted with water (50 ml) and extracted with chloroform (100 ml). The organic layer was washed with water, dried (MgSO4), and concentrated to dryness to give a brown syrup. The syrup was purified by flash chromatography on silica gel (elution with chloroform) to give 3-butyl-6-chloro-1-(4-methoxybenzyl)uracil as an oil. To a solution of the oil in ethanol (50 ml) was added hydrazine hydrate (20 ml) and the mixture was stirred at room temperature for 2 hours. The solution was concentrated under reduced pressure to give crude crystals, which were recrystallized from 70% ethanol to give pale yellow crystals (4.23 g, 54%), m.p. 167°-170° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O-:11])=[O:10].[Na+].Cl.[NH:14]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@H:15]([C:23](ON1C(=O)CCC1=O)=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.S(=O)(=O)(O)O>O1CCOCC1>[C:36]([O:35][C:33]([NH:14][C@H:15]([C:23]([CH:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH2:1])[C:9]([OH:11])=[O:10])=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:34])([CH3:38])([CH3:39])[CH3:37]
Reactant: NCCCCCCCC(=O)[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)C(CCCCCCN)C(=O)O
Temperature: 0 °C
Yield: 43 %

Procedure:
To a 250 mL round bottom flask equipped with an addition funnel was added a solution of sodium 8-aminocaprylate (14.61 mmol, 32.5 mL, 1.2 equiv). The pH of the solution was adjusted to 8.2 by addition of concentrated HCl. The solution was cooled in an ice-bath. Boc-Phe-OSu (12.42 mmol, 4.50 g, 1.0 equiv) was dissolved in 1,4-dioxane (20 mL) and added dropwise. The mixture was stirred in the ice-bath for 30 min and at ambient temperature for 12 h. The solution was acidified with 1 M sulfuric acid (80 mL) and extracted with ether (100+50 mL). The combined organic layers were washed with water (40 mL), dried and evaporated to give a pale yellow oil. The oil was triturated with hexanes (3×50 mL) to afford (N-tert-butoxycarbonylphenylalanyl)-8-aminocaprylic acid (5) (2.17 g, 43%) as a colorless solid.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[C:32](Cl)(=[O:34])[CH3:33]>>[C:32]([N:29]1[CH2:30][CH2:31][C@@H:27]([NH:26][C:24]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:8]4[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:15]=3[NH:22][C:21]=2[CH3:23])=[O:25])[CH2:28]1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CCNC1
Agent: Cl
Product: CC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f15) and commercially acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:6]([CH2:14][C:15]2[CH:16]=[C:17]([CH2:23][C:24]([OH:26])=[O:25])[CH:18]=[CH:19][C:20]=2[O:21][CH3:22])=[C:5]([CH3:27])[N:4]=1.O1CCOC[CH2:29]1>CO>[NH2:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:6]([CH2:14][C:15]2[CH:16]=[C:17]([CH2:23][C:24]([O:26][CH3:29])=[O:25])[CH:18]=[CH:19][C:20]=2[O:21][CH3:22])=[C:5]([CH3:27])[N:4]=1
Reactant: C1COCCO1
Reactant: CCCCNc1nc(N)nc(C)c1Cc1cc(CC(=O)O)ccc1OC
Agent: Cl
Solvent: CO
Product: CCCCNc1nc(N)nc(C)c1Cc1cc(CC(=O)OC)ccc1OC
Temperature: 60 °C

Procedure:
4M HCl in dioxane (1 mL) was added to a stirred suspension of the product from step (iv) (650 mg) in MeOH (2 mL). The suspension was heated at 60° C. for 2 h. The solvent was evaporated under reduced pressure to give the subtitle compound as a brown solid, 630 mg.
Reaction SMILES: Cl.[CH2:2]([CH2:5][NH2:6])[CH:3]=[CH2:4].[O:7]1[C:11]2([CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1.[C-:18]#[N:19].[K+]>CO.O>[CH2:2]([CH2:5][NH:6][C:14]1([C:18]#[N:19])[CH2:15][CH2:16][C:11]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:12][CH2:13]1)[CH:3]=[CH2:4]
Reactant: [C-]#N
Reactant: C=CCCN
Reactant: O=C1CCC2(CC1)OCCO2
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: C=CCCNC1(C#N)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 65 h
Yield: 93.4 %

Procedure:
A mixture of 9 ml water, 5.3 ml hydrochloric acid (32 per cent by weight), 8 ml methanol, 17.5 g allylmethylamine, 8.00 g 1,4-dioxaspiro[4.5]decan-8-one and 8.0 g potassium cyanide was stirred for 65 hours at room temperature. The yellowish-white suspension obtained was extracted four times with 25 ml diethyl ether each time, the combined extracts were dried over sodium sulfate, filtered and concentrated and the residue was largely freed from solvent residues in vacuo. 11.3 g 8-(allylmethylamino)-1,4-dioxaspiro[4.5]decane-8-carbonitrile were obtained as a pale brown liquid.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH2:32][CH2:33][CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:29])[F:30])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:32][CH2:33][CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:4]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 33.8 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 170 mg, 0.394 mmol), tert-butyl 2-aminoethylcarbamate (95 mg, 0.591 mmol), 4-methylmorpholine (159 mg, 1.577 mmol), and HATU (195 mg, 0.512 mmol) were dissolved in DMF (1 mL). The reaction mixture was stirred for 1 h and then was purified by prep HPLC (PHENOMENEX® Luna 5u 21×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 25 mL/min, 220 nM, product retention=31.6 min) to provide (R/S)-tert-butyl 2-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)ethylcarbamate (80 mg, 0.133 mmol, 33.6% yield): LCMS=474.1 [M+H−C5H9O2]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.17 (2 H, d, J=8.35 Hz), 7.51-7.74 (7 H, m), 5.12 (1 H, s), 3.35 (2 H, br. s.), 3.17-3.22 (2 H, m), 1.43 (9 H, s); HPLC peak RT=9.8 min (Method A).
Reaction SMILES: COC([CH2:5][CH:6]([CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=O)=O.Cl.Cl.[NH2:23][C@H:24]([C:31]([NH:33][C@@H:34]([CH2:43][CH:44]([CH3:46])[CH3:45])[CH:35]([OH:42])[C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37])=[O:32])[CH2:25][C:26]1[N:30]=[CH:29][NH:28][CH:27]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C(N(CC)CC)C>[CH3:39][O:38][C:36]([N:30]1[C:26]([CH2:25][C@@H:24]([C:31]([NH:33][C@@H:34]([CH2:43][CH:44]([CH3:46])[CH3:45])[CH:35]([OH:42])[C:36]([O:38][CH:39]([CH3:40])[CH3:41])=[O:37])=[O:32])[NH:23][C:7](=[O:9])[CH:6]([CH2:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[CH3:5])=[CH:27][N:28]=[CH:29]1)=[O:37]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1c[nH]cn1)C(O)C(=O)OC(C)C
Reactant: COC(=O)CC(Cc1cccc2ccccc12)C(=O)O
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)n1cncc1C[C@H](NC(=O)C(C)Cc1cccc2ccccc12)C(=O)N[C@@H](CC(C)C)C(O)C(=O)OC(C)C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
To a solution of 28 mg of 3-methoxycarbonyl-2-(1-naphthylmethyl)propionic acid and 50 mg of isopropyl (2RS,3S)-3-(L-histidyl)amino-2-hydroxy-5-methylhexanoate dihydrochloride were added successively 0.026 ml of diphenylphosphoryl azide and 0.046 ml of triethylamine, and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, and a 5% aqueous sodium bicarbonate solution was added to the residue. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1 by volume) to obtain 20 mg of isopropyl (2RS,3S)-3-[3-(methoxycarbonyl)-2-(1-naphthylmethyl)propionyl-L-histidyl]amino-2-hydroxy-5-methylhexanoate as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)[CH3:2].[CH:12]1([NH:18][OH:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N+:18]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[O-:19])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C=O)cc1
Reactant: ONC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOc1ccc(C=[N+]([O-])C2CCCCC2)cc1
Yield: 84.3 %

Procedure:
A solution of 4-ethoxybenzaldehyde (6.62 g, 44.1 mmol) in 200 mL of benzene was refluxed with N-cyclohexylhydroxylamine (6.61 g, 57.4 mmol) in the presence of p-toluenesulfonic acid (0.8 g, 4 mmol) for 72 h. After rotary evaporation, the residue was purified by recrystallization from hexanes and ethylene glycol dimethyl ether (100 mL, 3:1, v:v) to give the title compound (9.2 g, 84% yield) as a solid, m.p. 124.0° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:18][CH2:17][NH:16][C:15]2=[O:19])[CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]1[CH:9]=[C:10]([N:14]2[CH2:18][CH2:17][NH:16][C:15]2=[O:19])[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(N2CCNC2=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cccc(N2CCNC2=O)c1

Procedure:
A solution of [3-(2-oxo-imidazolidin-1-yl)-phenyl]-carbamic acid tert-butyl ester (0.88 g, 3.2 mmol) and trifluoroacetic acid (2 ml) in dichloromethane (10 ml) were stirred at room temperature for 5 hours. The reaction was quenched with sodium carbonate (20 ml) and extracted with dichloromethane (3×50 ml). The combined organics were dried (magnesium sulphate) and concentrated in vacuo (0.54 g, 96%). HPLC retention time 1 min. Mass spectrum (ES+) m/z 178 (M+H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]([NH:11][CH2:12][C:13]([O:15]C2C=CC([N+]([O-])=O)=CC=2)=O)=[O:10])=[CH:3][CH:2]=1.[NH2:25][C@H:26]([C:28]([N:30]1[CH2:41][CH2:40][CH2:39][C@H:31]1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:29])[CH3:27].C(Cl)(Cl)Cl.CO>C(OCC)(=O)C>[NH:11]([C:9]([O:8][CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)=[O:10])[CH2:12][C:13]([NH:25][C@H:26]([C:28]([N:30]1[CH2:41][CH2:40][CH2:39][C@H:31]1[C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])=[O:29])[CH3:27])=[O:15]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reactant: O=C(CNC(=O)OCc1ccccc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@H](NC(=O)CNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reaction time: 20 h

Procedure:
1.65 g of Z-Gly-ONP and 1.09 g of H-Ala-Pro-OtBu in 20 ml of ethyl acetate are allowed to stand for one hour at 0° C. and 20 hours at room temperature. The mix is then diluted with ethyl acetate, washed with 50% saturated potassium carbonate solution and with water, dried over sodium sulphate and evaporated. 2.06 g of an oil which is homogeneous according to thin layer chromatography result. Rf = 0.8 in the system chloroform-methanol (1:1) on silica gel.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:16][S:15][CH2:14][CH:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=3)[NH:12]2)=O)=[CH:4][C:3]=1[O:27][CH3:28]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH:11]2[CH2:16][S:15][CH2:14][CH:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=3)[NH:12]2)=[CH:4][C:3]=1[O:27][CH3:28]
Reactant: COc1cc(NC(=O)C2CSCC(c3ccc(OC)c(OC)c3)N2)ccc1Cl
Solvent: Cc1ccccc1
Product: COc1cc(NCC2CSCC(c3ccc(OC)c(OC)c3)N2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To an ice chilled suspension containing 5-(3,4-dimethoxy-phenyl)-thiomorpholine-3-carboxylic acid (4-chloro-3-methoxy-phenyl)-amide n(71 mg, 0.17 mmol, 1.0 equivalents) in toluene (1.5 ml) was added a 0.5M solution of alane (1.6 ml, 0.8 mmol, 4.8 equivalents). The reaction was stirred at room temperature for 2 hours. The reaction was quenched with 1N NaOH and extracted 3 times with dichloromethane. The dichloromethane extracts were dried with MgSO4, filtered and concentrated to yield (4-chloro-3-methoxy-phenyl)-[5-(3,4-dimethoxy-phenyl)-thiomorpholine-3-ylmethyl]-amine as an oil (65 mg, 95% yield). H1 NMR (400 MHz, CDCl3): 7.11 (1H, d), 6.93 (2H, m), 6.80 (1H, m), 6.19 (m, 2H), 3.86 (10H, m), 3.19 (3H, m), 2.80 (2H, m), 2.50 (2H, m). (LC-MS): Calculated for C20H25ClN2O3S 409.13, found 409.23.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[C:7]([CH3:8])=[CH:6][C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([S:13]([NH2:16])(=[O:15])=[O:14])[C:4]=2[O:3]1.N12CCCN=C1CCCCC2.[CH3:29][O:30][C:31]1[N:36]=[C:35]([CH3:37])[N:34]=[C:33]([N:38](C2C=CC=CC=2)[C:39](=O)[O-:40])[N:32]=1>O1CCOCC1.C(#N)C>[O:17]=[S:2]1(=[O:1])[C:7]([CH3:8])=[CH:6][C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([S:13]([NH:16][C:39]([NH:38][C:33]3[N:32]=[C:31]([O:30][CH3:29])[N:36]=[C:35]([CH3:37])[N:34]=3)=[O:40])(=[O:14])=[O:15])[C:4]=2[O:3]1
Reactant: COc1nc(C)nc(N(C(=O)[O-])c2ccccc2)n1
Reactant: CC1=Cc2cccc(S(N)(=O)=O)c2OS1(=O)=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2cccc3c2OS(=O)(=O)C(C)=C3)n1
Reaction time: 1 h
Yield: 97.1 %

Procedure:
A mixture of 3.3 g of 2,2-dioxo-3-methyl-1,2-benzoxathiin-8-yl sulfonamide, 1.90 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene, 3.28 g of N-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)phenylcarbamate in a mixture of 25 ml of dioxan and 10 ml of acetonitrile is stirred at 20° C. to 25° C. for 1 hour. The solvents are evaporated and the residue is triturated with a mixture of 7 ml of 2N hydrochloric acid and 10 ml of water and then with 20 ml of ether. The precipitate is isolated by filtration and dried, affording 5.14 g of N-(2,2-dioxo-3-methyl-1,2-benzoxathiin-8-ylsulfonyl)-N'-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)urea of m.p. 203°-205° C.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][N:8]1[C:9]([S:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: COc1cccc(CBr)c1
Product: COc1cccc(Cn2c(Sc3cc(C)cc(C)c3)c(C(C)C)c(=O)[nH]c2=O)c1
Yield: 49.4 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 3-methoxybenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (203 mg, yield: 49.4%).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1.CO.O.C(=O)([O-])[O-].[K+].[K+]>S(=O)(=O)(O)O.CCOCC>[OH:7][CH2:8][CH2:9][O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccc(OCCOC2CCCCO2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: O=C(O)c1ccc(OCCO)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 7.7 g (37.7 mmol) of 4-(2-tetrahydropyranyloxyethoxy)benzoic acid and 31 ml (754 mmol) of anhydrous methanol, at RT, is added 2 drops of conc. sulfuric acid. The mixture is stirred at RT for 1 day and is then rotoevaporated to near dryness. To the residue is added 100 ml water, 50 ml ether and 30 ml aqueous 15% potassium carbonate, and the mixture is stirred until the solid is dissolved. The organic phase is separated and discarded; 150 ml of ethyl acetate and 50 ml of aqueous 3 N sulfuric acid are added to the remaining aqueous phase. The aqueous phase is then separated and extracted with ethyl acetate (80 ml, 3×). The combined organic phases are washed with aqueous saturated sodium chloride (50 ml, 2×) and then dried over calcium sulfate. Removal of solvent by rotoevaporation gives 4-(hydroxyethoxy)benzoic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[C:23](=[O:25])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:26]N1C(=O)CCC1=O.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:12]([Br:26])=[CH:11][C:10]=1[C:23](=[O:25])[CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
51.2 g of 1-(2,4-Bis-benzyloxy-phenyl)ethanone (0.154 mol, 1 eq) were dissolved in 250 ml DMF. 27.42 g N-bromosuccinimide (0.154 mol, 1 eq) in 100 ml DMF were added dropwise. The mixture was stirred at room temperature over night. The reaction mixture was poured onto 700 ml of water and the precipitate filtered off. The filter cake was rinsed with water and the colourless solid was recrystallised from 370 ml acetonitrile.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]2[CH2:14][N:15](CC3C=CC=CC=3)[CH2:16][CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]2[CH2:14][NH:15][CH2:16][CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC2CN(Cc3ccccc3)CC2C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2CNCC2C1
Yield: 99.8 %

Procedure:
2-Benzyloctahydropyrrolo[3,4-c]pyridine-5-carboxylic acid tert-butyl ester (Example A26, 24.98 g, 78.8 mmol) in 400 mL of methanol is treated with 2.5 g of 20% Pd/C and shaken for 20.5 hours under 50 PSI of hydrogen. The solution is filtered and concentrated to afford 17.8 g of the title compound as a solid. MS APCI: m/z 228 (MH+).
Reaction SMILES: [C:1]([CH:4]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][CH2:14][CH2:13][C:12]=2[CH:16]=1)[C:5]([OH:7])=[O:6])([OH:3])=[O:2].O.Cl[CH2:19][O:20][C:21](=[O:23])[CH3:22].C(OCC)(=O)C>[OH-].[Na+].CCOCC>[C:21]([O:20][CH2:19][O:6][C:5]([CH:4]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][CH2:14][CH2:13][C:12]=2[CH:16]=1)[C:1]([OH:3])=[O:2])=[O:7])(=[O:23])[CH3:22]
Reactant: O=C(O)C(C(=O)O)c1ccc2c(c1)CCO2
Reactant: CC(=O)OCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(=O)OCOC(=O)C(C(=O)O)c1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
α-Carboxy(2,3-dihydro-5-benzofuranyl)acetic acid (10 mmole) is dissolved in 50 ml of water containing 10 mmole of sodium hydroxide. This mixture is stirred for 30 minutes at room temperature and then 10 mmole of chloromethylacetate in 25 ml of ether is added. The temperature during the addition is 10° C.; after the addition is complete, the temperature is raised to 20° C. and the mixture stirred for an additional 30 minutes. The pH is adjusted to 2 and ethyl acetate is added. The organic phase is removed, dried over magnesium sulfate, filtered and evaporated to give the title compound.