Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].I[CH:18]([CH3:20])[CH3:19]>>[CH3:19][CH:18]([CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH3:20]
Reactant: CCCCC(=O)Cc1ccccc1
Reactant: CC(C)I
Agent: C[O-]
Agent: [Na+]
Product: CCCCC(=O)C(c1ccccc1)C(C)C
Temperature: 0 °C

Procedure:
To an ice-cold magnetically stirred mixture of 1-phenylhexan-2-one (Intermediate II-1) (7.04 gram, 0.04 mol) and sodium methoxide (4.32 g, 0.08 mol) was added dropwise 2-iodopropane (15 ml) in a nitrogen atmosphere. The resulting mixture was heated for 1 hour at reflux temperature. The obtained mixture was allowed to attain room temperature and concentrated. The resulting residue was taken up in diethyl ether and water. The diethyl ether layer was separated and successively washed with an aqueous Na2S2O3 solution and water. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was further purified using Sepacore equipment: (petroleum ether/diethyl ether=19/1 (v/v)) to give 2-methyl-3-phenyl-octan-4-one (Intermediate IIa-1) (3.52 gram) as a colorless oil; 1H-NMR (400 MHz, CDCl3) δ 0.66 (d, J=7, 3H), 0.81 (t, J=7, 3H), 0.96 (d, J=7, 3H), 1.10-1.24 (m, 2H), 1.36-1.54 (m, 2H), 2.29-2.47 (m, 3H), 3.30 (d, J=10 Hz, 1H), 7.20-7.33 (m, 5H). Rf (petroleum ether/diethyl ether=98/2 (v/v))˜0.25.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][CH2:7][CH2:8]P(OCC)(OCC)=O)[CH3:2].[Li+].CC([N-]C(C)C)C.[CH3:26][C:27]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([CH2:30][CH3:31])[CH:28]=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:6][CH2:7][CH3:8])=[CH:28][C:27]([CH3:26])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:30][CH3:31])[CH3:2]
Reactant: CCOC(=O)COCCP(=O)(OCC)OCC
Reactant: CCC(C)(C=O)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=CC(C)(CC)c1ccccc1)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 116 %

Procedure:
To a chilled (0° C.) solution of 7.4 g of (diethoxyphosphoryl)ethoxy acetic acid ethyl ester in 30 mL of THF was added 16 mL of a 1.8M solution of LDA. After 30 minutes, 4.2 g of 2-methyl-2-phenylbutyraldehyde in 30 mL of THF was added dropwise by syringe. The mixture was warmed to room temperature, quenched with saturated aqueous ammonium chloride, and extracted with diethyl ether. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to afford 8.3 g of 2-ethoxy4-methyl-4-phenylhex-2-enoic acid ethyl ester as an orange oil and a mixture of geometric isomers (2:1).
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[CH2:5]([Mg]Br)[CH3:6].C(OCC)C.[CH2:14]([C@H:16]1[C:20](=[O:21])[CH2:19][CH2:18][N:17]1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[CH3:15]>>[CH2:14]([C@H:16]1[C@@:20]([CH2:5][CH3:6])([OH:21])[CH2:19][CH2:18][N:17]1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[CH3:15]
Reactant: CC[Mg]Br
Reactant: CC[C@H]1C(=O)CCN1C(=O)OCc1ccccc1
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CCOCC
Product: CC[C@@H]1N(C(=O)OCc2ccccc2)CC[C@@]1(O)CC

Procedure:
By an operation in the same manner as in Reference Example 3 and using cerium chloride (8.58 g), 3 mol/L ethylmagnesium bromide—diethyl ether solution (9.6 mL) and benzyl (2S)-2-ethyl-3-oxopyrrolidine-1-carboxylate (2.37 g), the title compound was obtained as colorless oil (yield: 2.19 g, yield: 82%).
Reaction SMILES: [CH2:1]([C:4]1[C:9]2[N:10]=[C:11]([CH3:13])[O:12][C:8]=2[CH:7]=[CH:6][C:5]=1[OH:14])[CH:2]=[CH2:3].[C:15](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[CH2:1]([C:4]1[C:9]2[N:10]=[C:11]([CH3:13])[O:12][C:8]=2[CH:7]=[CH:6][C:5]=1[O:14][CH3:15])[CH:2]=[CH2:3]
Reactant: O=C([O-])[O-]
Reactant: C=CCc1c(O)ccc2oc(C)nc12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: C=CCc1c(OC)ccc2oc(C)nc12
Yield: 81.6 %

Procedure:
1.44 g of 4-allyl-5-hydroxy-2-methylbenzoxazole was dissolved in 5 ml of N,N-dimethylformamide and 5 ml of acetonitrile. Thereafter, 1.05 g of potassium carbonate and 0.55 ml of methyl iodide were successively added to the reaction solution. Approximately 16 hours later, water and ethyl acetate were added to the reaction solution, so as to separate an organic layer. The obtained organic layer was washed with a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure, and the residue was then purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain 1.26 g of the subject compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=O)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[CH3:12][CH:13]([CH3:29])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:18]=1)=[O:15]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:26]3[CH2:27][CH2:28][CH:23]([C:19]4[CH:18]=[C:17]([NH:16][C:14](=[O:15])[CH:13]([CH3:12])[CH3:29])[CH:22]=[CH:21][CH:20]=4)[CH2:24][CH2:25]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=Cc1ccc2c(c1)CCO2
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4c(c3)CCO4)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 2,3-dihydro-1-benzofuran-5-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 379.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:18]2[C:13](=[CH:14][C:15]([C:20](O)=[O:21])=[C:16]([Cl:19])[CH:17]=2)[S:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]2[N:30]([C:33]([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)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:31]=[CH:32][C:25]=12.[I-].ClC1C=CC=C[N+]=1C>>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:18]2[C:13](=[CH:14][C:15]([C:20]([NH:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]4[N:30]([C:33]([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)[C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)[N:31]=[CH:32][C:25]=34)=[O:21])=[C:16]([Cl:19])[CH:17]=2)[S:12][CH2:11][CH2:10]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCSc2cc(C(=O)O)c(Cl)cc21
Reactant: Nc1ccnc2c1cnn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Product: CC(C)(C)OC(=O)N[C@H]1CCSc2cc(C(=O)Nc3ccnc4c3cnn4C(c3ccccc3)(c3ccccc3)c3ccccc3)c(Cl)cc21
Yield: 86.2 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 53 using (S)-4-(tert-butoxycarbonylamino)-6-chloro-thiochromane-7-carboxylic acid (150 mg), 4-amino-1-triphenylmethylpyrazolo[3,4-b]pyridine (163 mg) and 2-chloro-1-methylpyridinium iodide (133 mg), the objective (S)-4-(tert-butoxycarbonylamino)-6-chloro-N-(1-triphenylmethylpyrazolo[3,4-b]pyridin-4-yl)thiochromane-7-carboxamide (262 mg) was obtained as a pale yellow amorphous solid.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[Cl:28][C:29]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:30]=1[CH:31]=O>ClCCCl.ClCCl>[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C@H:24]([NH:27][CH2:31][C:30]2[CH:33]=[CH:34][C:35]([Cl:37])=[CH:36][C:29]=2[Cl:28])[CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](NCc2ccc(Cl)cc2Cl)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.4 %

Procedure:
Alternatively, add sodium triacetoxyborohydride (1.6 g, 7.6 mmol) to a mixture of (S)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (1 g, 5.4 mmol) and 2,4-dichlorobenzaldehyde (2.8 g, 16.2 mmol) in 1,2-dichloroethane (10 mL) and stir overnight at room temperature. Dilute with dichloromethane and wash with saturated aqueous sodium chloride, dry (magnesium sulfate) concentrate and chromatograph on silica gel to give (S)-3-(2,4-dichlorobenzylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (865 mg, 33%). 1H NMR (400 MHz, CDCl3) 7.33-7.38 (2H, m), 7.23 (1H, d, J=7.82 Hz), 3.85 (2H, d, J=1.96 Hz), 3.45-3.56 (2H, m), 3.30-3.40 (2H, m), 3.19-3.10 (1H, m), 2.04 (1H, m), 1.74 (1H, m), 1.46 (9H, s), MS (ES): m/z=345 [M+].
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[OH:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:19]([O:18][C:16](=[O:17])[C:15]1[CH:21]=[CH:22][CH:23]=[C:13]([O:12][C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH:14]=1)[CH3:20]
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: CCOC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(Oc2ccc(F)cc2[N+](=O)[O-])c1
Temperature: 85 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
2,5-Difluoronitrobenzene (5.0 g, 31.4 mmol), ethyl 3-hydroxybenzoate (5.2 g, 31.4 mmol), and K2CO3 (8.7 g, 62.8 mmol) were added to DMF (50 mL). The solution was heated to 85° C. and stirred for 16 h. The reaction was cooled. The reaction was poured into distilled water and extracted with ethyl acetate. The combined organic layers were washed with distilled water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the crude title compound. The crude product was purified by silica gel column chromatography eluting with hexanes/ethyl acetate (90:10) to give the title compound (7.0 g, 73%).
Reaction SMILES: [BrH:1].C(OC([N:12]([CH2:46][CH2:47][C:48]1[C:56]2[S:55][C:54](=[O:57])[NH:53][C:52]=2[C:51]([OH:58])=[CH:50][CH:49]=1)[CH2:13][CH2:14][N:15]([CH:39]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)[C:16](=[O:38])[CH2:17][CH2:18][N:19]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)C(=O)OCC1C=CC=CC=1)=O)C1C=CC=CC=1.COC(C)(C)C>C(O)(=O)C>[BrH:1].[BrH:1].[CH:39]1([N:15]([CH2:14][CH2:13][NH:12][CH2:46][CH2:47][C:48]2[C:56]3[S:55][C:54](=[O:57])[NH:53][C:52]=3[C:51]([OH:58])=[CH:50][CH:49]=2)[C:16](=[O:38])[CH2:17][CH2:18][NH:19][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: O=C(OCc1ccccc1)N(CCC(=O)N(CCN(CCc1ccc(O)c2[nH]c(=O)sc12)C(=O)OCc1ccccc1)C1CCCCCC1)CCc1ccccc1
Agent: Br
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Product: O=C(CCNCCc1ccccc1)N(CCNCCc1ccc(O)c2[nH]c(=O)sc12)C1CCCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydrogen bromide (33% in acetic acid) (0.54 mL) was added to the product from step i) (0.238 g) in acetic acid (0.8 mL) at 0° C. The resulting solution was stirred at room temperature for 2 h then t-butyl methyl ether (3 mL) was added and the mixture stirred for 10 min. A gummy solid formed, which was filtered off and triturated with t-butyl methyl ether (4×3 mL) to form a pale orange solid (0.888 g). The solid was dried at 45° C. for 1 h then recrystallised from hot ethanol (˜3 mL) to afford the title product as a white solid (0.040 g).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:22]([NH:24][CH2:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35](=[O:43])[C:36]1[CH:41]=[C:40]([Br:42])[CH:39]=[CH:38][N:37]=1)=[O:27])=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14]C(OC(C)(C)C)=O)=O)(C)(C)C.[ClH:44].C(OCC)C>O1CCOCC1>[ClH:44].[ClH:44].[ClH:44].[NH2:8][C@H:9]([C:22]([NH:24][CH2:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35](=[O:43])[C:36]1[CH:41]=[C:40]([Br:42])[CH:39]=[CH:38][N:37]=1)=[O:27])=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)Nc1ccccc1C(=O)c1cc(Br)ccn1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: NCCCC[C@H](N)C(=O)NCC(=O)Nc1ccccc1C(=O)c1cc(Br)ccn1
Yield: 88 %

Procedure:
1.0 g of (Nα,Nε-ditertbutoxycarbonyl-L-lysyl)-N-(4-bromo-2-picolinoylphenyl)glycinamide was stirred for 1 hour in a solution of hydrogen chloride in dioxan (4-M). Diethyl ether was added and the solid which separated was filtered off, washed with diethyl ether and dried. The solid was dissolved in methanol and precipitated with ethyl acetate. The precipitate was dissolved in 20 ml of water and, after extraction with chloroform, the aqueous solution was lyophilised to yield 0.7 g (88%) of L-lysyl-N-(4-bromo-2-picolinoylphenyl)glycinamide trihydrochloride 1.5 H2O; [α]D20 = +20.1° (c = 1 in water).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].[OH-].[Cs+:10]>O>[C:1]([O-:8])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].[Cs+:10]
Reactant: CC(=O)CCC(=O)O
Agent: [Cs+]
Agent: [OH-]
Solvent: O
Product: CC(=O)CCC(=O)[O-]
Temperature: 65 °C

Procedure:
46.9 gr. of 99% pure levulinic acid is sluurried in 100 cc. distilled water. 97.3 g. of a 4.22 molar, pure cesium hydroxide solution is added and the temperature is raised to 65° C. to obtain complete solution. The solution is filtered through No. 40 filter paper to remove dust, etc. The solution is then evaporated on a hot plate to 200 g., which gives a 2 molar concentration, and it is then bottled.
Reaction SMILES: [CH2:1]([CH:3]([CH2:21][CH3:22])[C:4]([NH:6][C:7]1[S:8][C:9]2[CH2:20][CH2:19][CH2:18][CH2:17][C:10]=2[C:11]=1[C:12]([O:14]CC)=O)=[O:5])[CH3:2].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([NH:30][C:12]([C:11]1[C:10]2[CH2:17][CH2:18][CH2:19][CH2:20][C:9]=2[S:8][C:7]=1[NH:6][C:4](=[O:5])[CH:3]([CH2:1][CH3:2])[CH2:21][CH3:22])=[O:14])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1c(NC(=O)C(CC)CC)sc2c1CCCC2
Reactant: NCc1ccccc1
Product: CCC(CC)C(=O)Nc1sc2c(c1C(=O)NCc1ccccc1)CCCC2

Procedure:
The product of Example 14 and benzylamine were processed as in Examples 29A and 29B to afford the title compound. 1H NMR (300 MHz, CD3OD) δ ppm 0.91 (t, J=7.5 Hz, 6H), 1.52-1.71 (m, 4H), 1.77-1.89 (m, 4H), 2.16-2.29 (m, 1H), 2.64-2.75 (m, 4H), 4.56 (s, 2H), 7.21-7.29 (m, 1H), 7.31-7.37 (m, 4H); MS (DCI/NH3) m/z 385 (M+H)+; anal. calculated for C22H28N2O2S: C, 68.72; H, 7.34; N, 7.28. Found: C, 68.45; H, 7.49; N, 7.17.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH:15]2[C:19](O)=[O:20])=[C:5]([N+:30]([O-:32])=[O:31])[CH:4]=1.N>>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH:15]2[CH2:19][OH:20])=[C:5]([N+:30]([O-:32])=[O:31])[CH:4]=1
Reactant: COc1ccc(C(=Cc2cc(OC)c(OC)cc2[N+](=O)[O-])CN2CCCC2C(=O)O)cc1
Agent: N
Product: COc1ccc(C(=Cc2cc(OC)c(OC)cc2[N+](=O)[O-])CN2CCCC2CO)cc1

Procedure:
General procedure f from 40 (90%); dark oil; 1H NMR (400.13 MHz) δ 7.59 (s, 1H), 7.23 (d, J=4 Hz, 2H), 7.00 (s, 1H), 6.71 (d, J=4 Hz, 2H), 6.23 (s, 1H), 4.17 (d, J=7 Hz, 2H), 3.89 (s, 3H), 3.78 (d, J=7 Hz, 2H), 3.69 (s, 3H), 3.58 (m, 1H), 3.41 (s, 3H), 3.16 (m, 2H), 1.91 (m, 2H), 1.80 (m, 2H); MS (DCI/NH3) m/e: 415 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23](=[O:33])[NH:24][C:25]4[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=4[F:32])[CH:18]=3)[CH:13]=[CH:12][N:11]=2)[NH:7][CH:6]=1)=[O:4].[OH-].[Na+].O.Cl>C1COCC1>[F:32][C:26]1[CH:27]=[CH:28][C:29]([CH3:31])=[CH:30][C:25]=1[NH:24][C:23]([C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[O:16][C:14]1[CH:13]=[CH:12][N:11]=[C:10]([C:8]2[NH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:9]=2)[CH:15]=1)=[O:33]
Reactant: COC(=O)c1c[nH]c(-c2cc(Oc3cccc(C(=O)Nc4cc(C)ccc4F)c3)ccn2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)c2cccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)c2)c1
Temperature: 70 °C

Procedure:
To a stirred solution of 5-{4-[3-(2-Fluoro-5-methyl-phenylcarbamoyl)-phenoxy]-pyridin-2-yl}-1H-pyrrole-3-carboxylic acid methyl ester (140 mg, 0.3 mmol) in THF (8 ml) was added 5M NaOH solution (1 ml, 5 mmol). The mixture was heated at 70° C. for 3 hours, cooled to room temp, and poured into 100 ml of water. 2M HCl was added until pH=4. The precipitates were filtered, washed with water, and dried to give 5-{4-[3-(2-Fluoro-5-methyl-phenylcarbamoyl)-phenoxy]-pyridin-2-yl}-1H-pyrrole-3-carboxylic acid as white solid. Yield: 120 mg, 92%.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][NH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH3:14]I>>[CH3:14][N:9]1[N:10]=[N:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8]1
Reactant: CI
Reactant: c1ccc(-c2nn[nH]n2)cc1
Agent: [Na+]
Agent: [OH-]
Product: Cn1nnc(-c2ccccc2)n1
Temperature: 0 °C
Yield: 45.6 %

Procedure:
5-phenyl-2-H-tetrazole (4 g, 27.36 mmol) was taken into NaOH (2.18 g, 54 mmol, dissolved in 10 ml of water), cooled to 0° C., methyl iodide (8.5 g, 60 mmol, dissolved in 40 ml acetone) was added and the reaction mixture was refluxed at 55° C. for 2 hours. The solvent was evaporated and the residue was dissolved in benzene. The benzene layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography using 60-120 mesh size silica gel (10% ethyl acetate in pet-ether as eluent) to obtain 2-methyl-5-phenyl-2H-tetrazole as white solid (2 g, 46%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH:15]1([C:18](Cl)=[O:19])[CH2:17][CH2:16]1>CCOC(C)=O>[CH:15]1([C:18]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=2)=[O:19])[CH2:17][CH2:16]1
Reactant: Nc1ccc(S)cc1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(S)cc1)C1CC1
Reaction time: 8 h
Yield: 88 %

Procedure:
To 4-aminothiophenol (9.4 g, 75.0 mmol, 1.5 equiv) and pyridine (8.09 mL, 100.0 mmol, 2 equiv) at 0° C. was added cyclopropanecarbonyl chloride (4.58 mL, 50.0 mmol, 1 equiv) drop wise. The reaction was stirred from 0° C. to room temperature for overnight, diluted with EtOAc (200 mL), washed with 1 N HCl (50 mL×4), dried over Na2SO4, concentrated, and dried under vacuum to yield the compound 5 as a off-white solid (8.5 g, 88%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[C@H:10]([CH2:27][CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[NH:11][C:12](=[O:26])[C@H:13]([C:22]([CH3:25])([CH3:24])[CH3:23])[NH:14]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:46]([O:50][C:51]([NH:53][C@H:54]([C:63]([OH:65])=O)[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[CH3:62])=[O:52])([CH3:49])([CH3:48])[CH3:47].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N1CCOCC1)C>C(#N)C.ClCCl>[CH2:1]([O:8][C:9](=[O:33])[C@H:10]([CH2:27][CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[NH:11][C:12](=[O:26])[C@H:13]([C:22]([CH3:24])([CH3:23])[CH3:25])[NH:14][C:63](=[O:65])[C@H:54]([CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[CH3:62])[NH:53][C:51]([O:50][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:52])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N[C@@H](CC1CCCC1)C(=O)OCc1ccccc1)C(C)(C)C
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: Cc1ccccc1C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](CC1CCCC1)C(=O)OCc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
993 mg (2.16 mmol) of N-[N-(tert-butoxycarbonyl)-3-methyl-L-valyl]-3-cyclopentyl-L-alanine benzyl ester and 1.23 g (6.47 mmol) of 4-toluenesulphonic acid hydrate were dissolved in 20 ml of acetonitrile and the solution was stirred at room temperature for 2 hours. The solvent was removed by evaporation and the residue was triturated with diethyl ether and filtered off. The solid obtained was added to a mixture of 602 mg (2.16 mmol) of N-(tert-butoxycarbonyl)-2-methyl-L-phenylalanine, 338 mg (2.21 mmol) of 1-hydroxybenzotriazole, 576 mg (3 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 345 mg (3 mmol) of N-ethylmorpholine in 20 ml of dichloromethane and stirred at room temperature for 18 hours. The solution was extracted with 2M hydrochloric acid and saturated sodium bicarbonate solution, then dried over anhydrous magnesium sulphate and evaporated. Chromatography of the residue on silica gel using ethyl acetate/ petrol (3:7) for the elution gave 990 mg of N-[N-[N-(tert-butoxycarbonyl)-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-3-cyclopentyl-L-alanine benzyl ester as a white solid; MS: m/e 622 [M+H].
Reaction SMILES: [ClH:1].[C:2]([C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][CH2:8][C:9]2=O)(=[NH:4])[NH2:3].Cl.[NH2:16][N:17]1[CH2:21][CH2:20][N:19]=[C:18]1[NH2:22].CC1C=CC(S(O)(=O)=O)=CC=1.C=CC1C=CC=CC=1.C(C1C=CC=CC=1C=C)=C>O>[ClH:1].[ClH:1].[C:2]([C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][CH2:8][C:9]2=[N:16][N:17]1[CH2:21][CH2:20][N:19]=[C:18]1[NH2:22])(=[NH:4])[NH2:3]
Reactant: NC1=NCCN1N
Reactant: N=C(N)c1cccc2c1CCC2=O
Agent: C=Cc1ccccc1C=C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: C=Cc1ccccc1
Product: N=C(N)c1cccc2c1CCC2=NN1CCN=C1N
Reaction time: 18 h

Procedure:
A solution of 0.24 g (0.001 mol) of 4-amidino-2,3-dihydro-1H-inden-1-one hydrochloride and 0.136 g (0.001 mol) of 1,2-diamino-4,5-dihydro-imidazole hydrochloride [m.p. 245°-246° C., prepared from the corresponding p-toluenesulfonate salt, see EP 0 327 919, Example 12, by ion exchange on ®Amberlite IRA-400 (anion exchanger based on a styrene/divinylbenzene polymer with quaternary ammonium groups in the Cl- form; Fluka, Buchs, Switzerland)] in 3 ml of water is left to stand at room temperature for 18 hours. The product that has crystallized out is filtered off with suction and recrystallized from water, yielding the title compound (monohydrate), m.p. 280° C. (decomp.), 1 H-NMR (DMSO/D2O): δ=8.17 (d, 1H); 7.66 (d, 1H); 7.54 (t, 1H); 4.18 (t, 2H); 3.70 (t, 2H); 3.25 (m, 2H); 3.13 (m, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:18]=[C:17]([CH3:19])[O:16][N:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:20][O:21][C:22]1[C:29]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)=[CH:28][C:25]([CH:26]=O)=[C:24]([O:35][CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[CH:23]=1.C[O-].[Li+].[ClH:47]>CN(C)C=O.CO.O>[ClH:47].[CH3:20][O:21][C:22]1[C:29]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)=[CH:28][C:25](/[CH:26]=[CH:2]/[C:1]([C:4]2[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]3[CH:18]=[C:17]([CH3:19])[O:16][N:15]=3)(=[O:11])=[O:12])=[CH:8][CH:9]=2)=[O:3])=[C:24]([O:35][CH2:36][CH2:37][N:38]2[CH2:39][CH2:40][O:41][CH2:42][CH2:43]2)[CH:23]=1
Reactant: CC(=O)c1ccc(S(=O)(=O)Nc2cc(C)on2)cc1
Reactant: COc1cc(OCCN2CCOCC2)c(C=O)cc1-c1cccs1
Agent: C[O-]
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OCCN2CCOCC2)c(/C=C/C(=O)c2ccc(S(=O)(=O)Nc3cc(C)on3)cc2)cc1-c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
4-Acetyl-N-(5-methylisoxazole-3-yl)benzenesulfonamide (Ex-1B, 0.30 g, 0.86 mmol) and 4-methoxy-2-(2-morpholin-4-ylethoxy)-5-thien-2-ylbenzaldehyde (Ex-14A, 0.24 g, 0.86 mmol) were dissolved in a dimethylformamide-methanol solution (6.0 mL, 7:3). After complete dissolution, lithium methoxide (0.13 g, 3.4 mmol) was added and the resulting orange slurry was stirred in the dark at room temperature for 1 h. Upon completion, as determined by HPLC, the mixture was diluted with water (8.0 mL), acidified with a 1 N hydrochloric acid solution, and extracted with ethyl acetate:tetrahydrofuran (1:1, 3×20 mL). The combined organic extracts were evaporated to dryness. The crude oil was taken up in ethanol (10 mL) and warmed to 60° C. to obtain complete dissolution and allowed to cool to room temperature. The resulting precipitate was collected on filter paper and dried in vacuo to yield 0.46 g (88%) of the title compound as a pale orange solid, mp>260° C. 1H-NMR (300 MHz, DMSO-d6) 8.34 (d, 2H, J=9.0 Hz), 8.32 (s, 1H), 8.12 (d, 1H, J=15.9 Hz), 8.03 (d, 2H, J=9.0 Hz), 7.93 (d, 1H, J=15.9 Hz), 7.69 (d, 1H, J=3.3 Hz), 7.56 (d, 1H, J=5.4 Hz), 7.15 (dd, 1H, J=5.4, 3.3 Hz), 6.92 (s, 1H), 6.18 (s, 1H), 4.65 (brs, 2H), 4.03 (s, 3H), 3.97 (brs, 4H), 3.69 (brs, 2H), 3.50–3.23 (brs, 4H), 2.31 (s, 3H). Anal. Calcd. for C30H32ClN3O7S2.H2O: C, 54.25; H, 5.16; N, 6.33; S, 9.66; Found: C, 54.10; H, 4.91; N, 6.39; S, 9.68. HRMS (ESI) Calcd. for C30H32ClN3O7S2: 610.1681 (—HCl) (M+H)+. Found: 610.1673.