Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[O:18])[CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19](I)[CH:20]([CH3:22])[CH3:21]>>[CH2:19]([N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][CH2:9][C:10]1=[O:18])[CH:20]([CH3:22])[CH3:21]
Reactant: O=C1CN=C(c2ccccc2)c2ccccc2N1
Reactant: CC(C)CI
Product: CC(C)CN1C(=O)CN=C(c2ccccc2)c2ccccc21

Procedure:
1,3-Dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (prepared according to the procedure of M. G. Bock et al., J Org Chem. 1987, 52, 3232-3239) was alkylated with isobutyl iodide using General Procedure 8-G to afford 1,3-dihydro-1-isobutyl-5-phenyl-2H-1,4-benzodiazepin-2-one.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:9]([C:10]([OH:12])=[O:11])[C:8]2([CH3:14])[CH3:13])=[CH:4][CH:3]=1.C(=O)(O)[O-].[K+].CS(O[CH2:27][C:28]1[NH:29][CH:30]=[CH:31][C:32]=1[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=O)=O>C1COCC1.CN(C=O)C.CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH:9]([C:10]([O:12][CH2:27][C:28]3[NH:29][CH:30]=[CH:31][C:32]=3[CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:11])[C:8]2([CH3:13])[CH3:14])=[CH:15][CH:16]=1
Reactant: CC1(C)C(Oc2ccc(F)cc2)C1C(=O)O
Reactant: CS(=O)(=O)OCc1[nH]ccc1Cc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC1(C)C(Oc2ccc(F)cc2)C1C(=O)OCc1[nH]ccc1Cc1ccccc1
Reaction time: 48 h

Procedure:
3-(4-Fluorophenoxy)-2,2-dimethylcyclopropanecarboxylic acid (3.40 mmol) is stirred together with 0.34 g (3.40 mmol) potassium bicarbonate in 10 ml THF/DMF (1:1) for 15 minutes. Then 3.40 mmol of 3-benzylpyrrolylmethyl methanesulfonate in 5 ml THF/DMF (1:1) is added and the mixture stirred for approximately 48 hours. The reaction is diluted with ether, washed with water (3X) and sat. NaCl, dried and solvent is removed. The crude product is purified by preparative TLC developing with 10% ethyl acetate/hexane to yield 3-benzylpyrrolylmethyl 3-(4-fluorophenoxy)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[F:12].O.[NH2:15][NH2:16]>C(O)C>[F:12][C:5]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:4]=1[C:3]([NH:15][NH2:16])=[O:2]
Reactant: NN
Reactant: COC(=O)c1ccc(OC)cc1F
Solvent: CCO
Solvent: O
Product: COc1ccc(C(=O)NN)c(F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.6 %

Procedure:
To a solution of 5.04 g (27.2 mmol) of 2-fluoro-4-methoxybenzoic acid methyl ester in ethanol (50 mL) are added 36.9 mL (408.6 mmol) of hydrazine hydrate. The reaction is stirred at room temperature for 15 h. The mixture is concentrated under reduced pressure and the solid is washed with DCM/heptane (2:1) to give 4.26 g (23.0 mmol) of 2-fluoro-4-methoxybenzoic acid hydrazide. Yield: 85%, ES-MS: m/z [M+H] 185.
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([O:39][CH3:40])[C:31]=2[C:35]([F:38])([F:37])[F:36])[C:26]=1[C:41](O)=[O:42].Cl.[C:45]([O:49][C:50](=[O:53])[CH2:51][NH2:52])([CH3:48])([CH3:47])[CH3:46].C(N(CC)CC)C>CN(C)C=O.O>[Cl:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([O:39][CH3:40])[C:31]=2[C:35]([F:37])([F:38])[F:36])[C:26]=1[C:41]([NH:52][CH2:51][C:50]([O:49][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:53])=[O:42]
Reactant: COc1ccc2c(C(=O)O)c(Cl)ccc2c1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc2c(C(=O)NCC(=O)OC(C)(C)C)c(Cl)ccc2c1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
1-Hydroxybenzotriazole hydrate (2.45 g, 1.5 eq) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.78 g, 1.2 eq) was added to a stirred solution of 2-chloro-6-methoxy-5-(trifluoromethyl)naphthoic acid (3.69 g, 12.11 mmol, prepared by the process of Step 3, Example 12) in dry dimethylformamide (78 mL). After stirring 11/2 hours at room temperature, glycine t-butyl ester hydrochloride (4.06 g, 2 eq) and triethylamine (dried over KOH, 5.8 mL, 3.3 eq) were added. After stirring 3 hours the reaction mixture was diluted with water (1 L) and extracted with ether (3×350 mL). Silica gel was added to the extracts and the solvent was removed. The absorbate was flash chromatographed (70:30 petroleum ether:ethyl acetate) to give the title compound as a white solid (3.95 g, 80%), m.p. 166°-167° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:5]=[CH:6][C:7]([OH:9])=[O:8].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:14][O:13][C:12]1[CH:11]=[CH:10][C:4]([CH:5]=[CH:6][C:7]([O:9][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:8])=[CH:3][C:2]=1[O:1][CH2:11][CH2:12][CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(C=CC(=O)O)cc1O
Reactant: CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCOC(=O)C=Cc1ccc(OC)c(OCCCCC)c1
Temperature: 90 °C
Yield: 217.7 %

Procedure:
3-Hydroxy-4-methoxycinnamic acid (9.7 g, 0.050 mol, 1.0 eq) was dissolved in DMF (90 ml). 1-Bromopentane (22.7 g, 0.150 mol, 3.0 eq) and anhydrous potassium carbonate (41.5 g, 0.30 mol, 6.0 eq) were successively added to this solution, and the mixture was stirred under heating at 90° C. for 3 hours. This reaction mixture was cooled to room temperature, and anhydrous potassium carbonate was filtered off. Water (200 ml) was added to the filtrate, and the mixture was exracted twice with ethyl acetate (200 ml). The organic layers were combined, washed with saturated brine (300 ml) and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (n-hexane/ethyl acetate=15/1-10/1) to give pentyl 4-methoxy-3-pentyloxycinnamate (18.2 g, 100%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([O:4][Na])=[O:3].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1C(=O)C.OO.C([O-])([O-])=O.[K+].[K+]>C(O)(=O)C.CCOCC.O>[C:2]([O:4][C:12]1[CH:13]=[C:8]([O:7][CH3:6])[CH:9]=[CH:10][C:11]=1[O:14][CH3:15])(=[O:3])[CH3:1]
Reactant: COc1ccc(OC)c(C(C)=O)c1
Reactant: CC(=O)O[Na]
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(OC)c(OC(C)=O)c1
Temperature: 40 °C
Reaction time: 144 h
Yield: 787.2 %

Procedure:
CH3COONa (0.7 g, 0.009 mol) was added under stirring to a solution of 2′,5′-dimethoxyacetophenone (CAS 1201-38-3, 45 g, 0.25 mol) in acetic acid (50 mL). A 50% solution of H2O2 in H2O (43 g, 0.62 mol) was added dropwise at 40° C. The reaction mixture was stirred at 40° C. for 144 h. Then it was cooled, diluted with ether (150 mL) and H2O (100 mL), and alkalized to pH 6 with a saturated solution of K2CO3. The layers were separated. The organic one was washed with water (2×100 mL), brine, dried, and evaporated. The residue was recrystallized from ether to give the title compound (13.9 g, 28%) as white crystals. LCMS data: 197.0 (M+H)+ and 155.1, 156.1 (M-Ac+H) (calculated for C10H12O4 196.2). 1H NMR data (DMSO-d6): 7.04 (d, 1H, J=9.0 Hz, Ar—H), 6.80 (dd, 1H, J1=3.2 Hz, J2=9.0 Hz, Ar—H), 6.72 (d, 1H, J=2.9 Hz, Ar—H), 3.70 (s, 3H, —OCH3), 3.69 (s, 3H, —OCH3), 2.24 (s, 3H, —COCH3).
Reaction SMILES: [C:1]([C:9]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.O>[OH:8][CH:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:11][CH2:10]1
Reactant: CCOC(=O)C1(C(=O)c2ccccc2)CC1
Reactant: [H][H]
Solvent: O
Solvent: CO
Product: CCOC(=O)C1(C(O)c2ccccc2)CC1
Temperature: 70 °C
Yield: 694.6 %

Procedure:
(S)-tBuBisP*-RuBr2 (25 mg) was placed in a reaction vessel and deaerated. After substitution with argon, a mixture of ethyl 1-benzoylcyclopropanecarboxylate (3.3 g, 1.0 mmol) and methanol-water (10/1) (33 ml) was added. The mixture was stirred at 70° C. and hydrogen pressure (6 kg/cm2) for 24 h, after which the reaction mixture was concentrated. This was concentrated to dryness, diluted with ethyl acetate, washed with water and purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the title compound (1.53 g, 46.3%) as a colorless oil. The enantiomer excess of this product was measured by high performance liquid chromatography (Condition F) and found to be 85%.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])=[CH:7][CH:6]=1.[CH2:25]([C:28]1[C:32]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:31][NH:30][N:29]=1)[CH2:26][CH3:27].CN(C)C=O>O>[CH3:16][C:15]1[O:14][C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:12][C:11]=1[CH2:10][O:9][C:8]1[CH:23]=[CH:24][C:5]([CH2:4][N:30]2[CH:31]=[C:32]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:28]([CH2:25][CH2:26][CH3:27])=[N:29]2)=[CH:6][CH:7]=1
Reactant: CCCc1n[nH]cc1CCC(=O)OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1CCC(=O)OCC
Reaction time: 12 h
Yield: 53.5 %

Procedure:
Sodium hydride (60%, oily, 110 mg) was added to a mixture of 4-[(4-chloromethylphenoxy)methyl]-5-methyl-2-phenyloxazole (910 mg), ethyl 3-(3-propyl-1H-pyrazol-4-yl)propionate (500 mg) and N,N-dimethylformamide (10 ml), which was stirred for 12 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-propyl-1H-pyrazol-4-yl]propionate (620 mg, yield: 53%) was obtained as a colorless oily substance.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([C@@H:7]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]2)[CH2:6][CH2:5]1.Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][N:16]=1.C(O)(C)C>O1CCCC1.O>[CH3:3][C:4]1([C@@H:7]2[CH2:12][CH2:11][C@H:10]([O:13][C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=[CH:17][N:16]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:6]1
Reactant: Clc1ncnc2ccccc12
Reactant: CC1([C@H]2CC[C@@H](O)CC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: CC1([C@H]2CC[C@@H](Oc3ncnc4ccccc34)CC2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
0.32 g (10.8 mmol) of sodium hydride (80% dispersion in mineral oil) was added to a solution of 1.7 g (7.9 mmol) of cis-4-(1-methylcyclopropyl)cyclohexanol in 20 ml of tetrahydrofuran, and the mixture was heated under reflux for 3 hours. It was then cooled to room temperature, 1.2 g (7.2 mmol) of 4-chloroquinazoline dissolved in 5 ml of tetrahydrofuran were added, and the mixture was heated under reflux for 2 hours. After cooling to room temperature, isopropanol was added to the reaction solution, which was subsequently stirred for 15 minutes and poured into water, after which extraction was carried out with diethyl ether. The organic phase was dried and concentrated. The residue was purified by chromatography on silica gel with petroleum ether/ethyl acetate 3:1. 1.2 g (62% of theory) were obtained of a colorless oil, which gradually solidified.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].Cl[C:6]1[N:14]=[C:13](Cl)[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].[CH2:16]([OH:18])[CH3:17]>>[CH2:2]([O:1][C:6]1[N:14]=[C:13]([O:18][CH2:16][CH3:17])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])[CH3:3]
Reactant: CCO
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: CC[O-]
Agent: [Na+]
Product: CCOc1ccc(C(=O)O)c(OCC)n1
Temperature: 170 °C

Procedure:
A solution of sodium ethoxide (23.3 mL) was added to a solution of 2,6-dichloronicotinic acid (2.00 g) in ethanol (10 mL). The mixture was heated in a sealed vessel at 170° C. for 1 day. After cooling, the mixture was concentrated in vacuo and the residue taken in water and acidified with hydrochloric acid to pH 3. The precipitated solids were collected by filtration and washed with water to obtain the title compound (1.75 g) having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.Cl[C:20]([C:22]1[CH:41]=[CH:40][C:25]([CH2:26][CH2:27][N:28]([CH3:39])[C:29](=[O:38])[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:24][CH:23]=1)=[O:21]>C1(C)C=CC=CC=1>[CH2:31]([O:30][C:29]([N:28]([CH3:39])[CH2:27][CH2:26][C:25]1[CH:24]=[CH:23][C:22]([C:20]([NH:1][C:2]2[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[O:21])=[CH:41][CH:40]=1)=[O:38])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CN(CCc1ccc(C(=O)Cl)cc1)C(=O)OCc1ccccc1
Reactant: COC(=O)c1cccc(N)c1O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1cccc(NC(=O)c2ccc(CCN(C)C(=O)OCc3ccccc3)cc2)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
To a stirred solution of 4-(2-((benzyloxycarbonyl)(methyl)amino)ethyl)benzoic acid (2.0 g, 6.38 mmol) in anhydrous dichloromethane (30 mL) was added dropwise thionyl chloride (1.52 g, 12.76 mmol) at 0° C. After the addition, the solution was stirred at room temperature overnight. Solvent was removed in vacuum to give benzyl 4-(chlorocarbonyl)phenethyl(methyl)carbamate. To a stirred solution of methyl 3-amino-2-hydroxybenzoate (0.71 g, 4.25 mmol) and pyridine (0.19 mL, 10.2 mmol) in anhydrous toluene (20 mL) was added dropwise a solution of benzyl 4-(chlorocarbonyl)phenethyl(methyl)carbamate (1.7 g, 5.1 mmol) in anhydrous toluene (5 mL). After the addition, the mixture was stirred at room temperature 30 min, then 80° C. for 1 h. The mixture was diluted with toluene, washed with water (30 mL×3), 1N hydrochloric acid (30 mL×3), brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography ((silica gel, petroleum ether/ethyl acetate 15:1 to 4:1), to obtain methyl 3-(4-(2-((benzyloxycarbonyl)(methyl)amino)ethyl)benzamido)-2-hydroxybenzoate (1.9 g, yield 97%) as yellow oil. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.82-2.87 (m, 5H), 3.49-3.53 (t, J=7 Hz, 2H), 3.94 (s, 1H), 4.98-5.06 (d, J=32 Hz, 2H), 6.98-7.02 (t, J=8 Hz, 1H), 7.26-7.39 (m, 7H), 7.66-7.68 (d, J=7.6 Hz, 1H), 7.89-7.91 (m, 2H), 7.94-7.96 (d, J=8 Hz, 1H), 9.61 (s, 1H), 10.92 (s, 1H); LC-MS (ESI) m/z: 463 (M+1)+.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:28].[NH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=1>C1COCC1>[O:28]=[C:4]1[C:3](=[CH:2][NH:29][C:30]2[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=2)[C:11]2[C:6](=[CH:7][C:8]([C:12](=[O:13])[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[O:22])[CH:15]=3)=[CH:9][CH:10]=2)[NH:5]1
Reactant: O=C1Nc2cc(C(=O)c3cccc(NC(=O)c4cccs4)c3)ccc2C1=CO
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: C1CCOC1
Product: O=C1Nc2cc(C(=O)c3cccc(NC(=O)c4cccs4)c3)ccc2C1=CNc1ccc(C(=O)O)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
A small screw cap test tube was charged with Thiophene-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 45, 80 mg, 0.2049 mmol) and THF (2 mL). To the resulting solution was added 4-Amino-benzoic acid (34 mg, 0.248 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. The room temperature reaction mixture was concentrated in vacuo. The solid residue was recrystallized from EtOAc (5 mL) and Hexanes (2 mL) yielding the title compound in 81% yield (0.085 g, 0.1668 mmol).
Reaction SMILES: [C:1]1([S:7]([NH:10][C@@H:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][C:25](=[O:27])[NH:24][S:23]3(=[O:29])=[O:28])=[C:18]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:17]=2)[C:12]([OH:14])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:71][C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][C:73]=1[NH2:78]>CN(C=O)C>[NH2:71][C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][C:73]=1[NH:78][C:12](=[O:14])[C@@H:11]([NH:10][S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:8])=[O:9])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:26][C:25](=[O:27])[NH:24][S:23]2(=[O:28])=[O:29])=[C:18]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:17]=1
Reactant: O=C1CN(c2ccc(C[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: Nc1ccccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)[C@H](Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (S)-2-benzenesulfonylamino-3-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-propionic acid (110 mg, 0.2 mmol) in DMF (5 mL) is added diisopropylethylamine (0.038 mL, 0.22 mmol) and HATU (84 mg, 0.22 mmol). The mixture is stirred at RT for 10 min then a solution of 1,2-diaminobenzene (26 mg, 0.24 mmol) in DMF (1 mL) is added and stirring is continued for 48 h. The solvent is removed under reduced pressure to give the title compound which is used directly in the next step
Reaction SMILES: O[CH2:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:13])=O>C(Cl)(Cl)Cl>[ClH:13].[Cl:13][CH2:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cccnc1CO
Solvent: ClC(Cl)Cl
Product: COc1cccnc1CCl
Product: Cl
Reaction time: 1.5 h

Procedure:
(i) 3-Hydroxy-2-hydroxymethylpyridine (4.4 g) was added to a solution of sodium (0.81 g) in methanol (50 ml). The solvent was evaporated off, treated with toluene, re-evaporated and taken up in dimethylsulphoxide (88 ml) to which was added methyl iodide (5.0 g) in dimethylsulphoxide (12 ml) while the solution was stirred for 30 minutes at 18°. After standing overnight, the solvent was removed and the residue was partitioned between chloroform and water. The chloroform extract was evaporated and a solution of the residue in ethanol was treated with ethanolic hydrogen chloride to yield 2-hydroxymethyl-3-methoxypyridine hydrochloride (3.0 g) m.p. 208° dec. 2-Hydroxymethyl-3-methoxypyridine (4.2 g) was dissolved in chloroform (60 ml) and to the stirred solution was added thionyl chloride (6 ml). After stirring for 90 minutes and evaporation of the solvent, the residue was recrystallised from ethanol/ether to give 2-chloromethyl-3-methoxypyridine hydrochloride (5.1 g), m.p. 171.5° - 172.5°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=1)[O:8][CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])=[O:4]>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1.ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=1)[O:8][CH2:9][C:10]([OH:12])=[O:11])=[O:4]
Reactant: COC(=O)c1cccc(OCC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COC(=O)c1cccc(OCC(=O)O)c1
Yield: 86 %

Procedure:
A solution of t-butyl [3-(methoxycarbonyl)phenoxy]acetate in trifluoroacetic acid (1 kg), anisole (100 mL) and dichloromethane (1 L) was stirred at room temperature for 48 hours. The reaction mixture was concentrated and then the residue was crystallized from diisopropyl ether to obtain the title compound (467 g, 86%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH3:10])=[CH:5][N:4]=1)#[N:2].[C:11](O)([CH3:14])([CH3:13])[CH3:12].[OH-:16].[Na+]>OS(O)(=O)=O>[CH3:12][C:11]([NH:2][C:1]([C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH3:10])=[CH:5][N:4]=1)=[O:16])([CH3:14])[CH3:13]
Reactant: [OH-]
Reactant: CC(C)(C)O
Reactant: Cc1cnc(C#N)c(C)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1cnc(C(=O)NC(C)(C)C)c(C)c1
Temperature: 75 °C

Procedure:
To a stirred solution of 20.3 g (0.153 mol) of 2-cyano-3,5-dimethylpyridine in 100 mL of 20 mL of conc. H2SO4 within 10 minutes, followed by 20 mL of t-butanol over an additional 15 minutes. The solution was warmed at 75° C. for 30 minutes after which it was cooled to room temperature and basified with 25% NaOH. The product was extracted 3× with EtOAc (600 mL), which was combined and washed 1× with brine, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (31.26 g) as a yellowish oil.
Reaction SMILES: CO[C:3]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2C)=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH2:18][C:19]1[C:28]([NH2:29])=[CH:27][CH:26]=[C:25]2[C:20]=1[C:21]([OH:33])=[CH:22][C:23]([C:30]([OH:32])=[O:31])=[CH:24]2.Cl.Cl.N[C:37]1[CH:38]=C(S(O)(=O)=O)C2C([C:46]=1N)=C(O)C=CC=2>>[CH2:46]([C:14]1[CH:13]=[CH:12][C:11]([C:10]2[CH:9]=[CH:8][CH:7]=[C:4]([C:5]3[NH:29][C:28]4[CH:27]=[CH:26][C:25]5[C:20](=[C:21]([OH:33])[CH:22]=[C:23]([C:30]([OH:32])=[O:31])[CH:24]=5)[C:19]=4[N:18]=3)[CH:3]=2)=[CH:16][CH:15]=1)[CH2:37][CH3:38]
Reactant: Nc1cc(S(=O)(=O)O)c2cccc(O)c2c1N
Reactant: Nc1ccc2cc(C(=O)O)cc(O)c2c1N
Reactant: COc1c(C=O)cccc1-c1ccccc1C
Agent: Cl
Product: CCCc1ccc(-c2cccc(-c3nc4c(ccc5cc(C(=O)O)cc(O)c54)[nH]3)c2)cc1

Procedure:
Follow the procedure of example 1c) except substituting 4′-propylbiphenyl-3-carbaldehyde for 2-methoxy-3-(2′-methylphenyl) benzaldehyde and 5,6-diamino-4-hydroxynaphthalene-2-carboxylic acid for 3,4-diamino-5-hydroxy-1-naphthalene sulfonic acid dihydrochloride, the title compound was prepared as a solid (0.05 g, 99%). MS(ES) m/z 423 [M+H].
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10]O)[CH2:4][CH2:3]1.[C:12]([NH:19][C:20](=[N:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[S:21][CH3:22])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([CH2:8][CH2:9][CH2:10][N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:20](=[N:19][C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[S:21][CH3:22])[CH2:6][CH2:7]1
Reactant: CN1CCC(CCCO)CC1
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CSC(=NC(=O)OC(C)(C)C)N(CCCC1CCN(C)CC1)C(=O)OC(C)(C)C
Temperature: 2 °C
Reaction time: 0.5 h

Procedure:
To a 25 mL round bottom flask were added 3-(1-methyl-piperidin-4-yl) -propan-1-ol (0.23 g, 0.0014 mol), 1,3-di-Boc-2-methylisothiourea (0.42 g, 0.0014 mol), PPh3 (0.42 g, 0.0016 mol) and THF (anhydrous, 8.0 mL). The resultant, stirred stirring solution was cooled to 2.0° C. To the resultant solution was then added DEAD (0.27 mL, 0.0016 mol) drop wise. The reaction was aged cold for 30 min, warmed to room temperature and aged for 14 h. The THF was removed via rotovap and the residue taken up in MTBE (10 mL). The resultant solution was extracted with saturated aqueous NaHCO3 (2×10 mL) and diluted with hexanes (20 mL). After 10 min, the resultant slurry was filtered and the filtrate concentrated via rotovap. The residue was taken up in hexanes (25 mL) and filtered after 10 min. The filtrate was concentrated to yield N-[3-(1-methylpiperidin-4-yl)-propyl]-N,N′-di-Boc-methylisothiourea.