Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[S:17][C:16]([S:18][CH2:19][C:20]([O:22]CC)=[O:21])=[N:15][N:14]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].[OH-].[Na+].O>CO>[C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[S:17][C:16]([S:18][CH2:19][C:20]([OH:22])=[O:21])=[N:15][N:14]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCSc2nnc(SCC(=O)OCC)s2)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCc1c(OCCCSc2nnc(SCC(=O)O)s2)ccc(C(C)=O)c1O
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
To a mixture of 4.2 g of ethyl [[5-[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl]thio]-1,3,4-thiadiazol-2-yl]thio]acetate obtained in Example 14 and 30 ml of methanol was added 20 ml of an aqueous solution of 5% sodium hydroxide and the mixture was stirred for 30 minutes. Then, 30 ml of water was added to the reaction mixture and methanol was removed under reduced pressure. The residue thus formed was washed with ethyl acetate, acidified with diluted hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue thus formed was recrystallized from 90% ethanol to provide 3.07 g of [[5-[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl]thio]-1,3,4-thiadiazol-2-yl]thio]acetic acid. The properties of the compound thus obtained were same as those of the compound obtained in Example 21.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[C:1]([N:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N1CCC(=O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a 0° C. solution of 1.0 g of 1-tert-butylpiperidin-4-one (COMPOUND PPA-1) in 2 mL of THF was added 6.4 mL of a 1M solution of lithium aluminum hydride in THF dropwise. The mixture was stirred 10 min at rt, then quenched by careful addition of 0.2 mL of water, 0.2 mL of 15% aqueous NaOH, and 0.6 mL of water. The mixture was stirred vigorously for 30 min, then filtered and concentrated to yield the title compound.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[CH2:6][CH2:5]1.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1[NH:29][C:30](=[O:33])[CH2:31]Cl>>[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1[NH:29][C:30]([CH2:31][NH:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:14])[CH2:6][CH2:5]1)=[O:33]
Reactant: Cc1cccc(C)c1NC(=O)CCl
Reactant: NC1CCN(CCCC(=O)c2ccccc2)CC1
Agent: Cl
Product: Cc1cccc(C)c1NC(=O)CNC1CCN(CCCC(=O)c2ccccc2)CC1

Procedure:
4-Amino-1-(4-phenyl-4-oxobutyl) piperidine dihydrochloride (1.75g) was condensed with N-(2,6-dimethylphenyl) chloroacetamide (0.999) in the manner of Example 1 to give the title compound which was converted to the hydrochloride salt (1.85g), m.p. 276.8° Analysis: Found, C, 62.26; H, 7.48; N, 8.68; C25H33N3O2. 2HC1 requires C, 62.25; H, 7.34; N, 8.75%
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([O-:15])=O)=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K+].N1C=CC=CC=1.C(Cl)(=O)C([Cl:26])=O>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:12]([C:13]([Cl:26])=[O:15])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])c1nnnn1Cc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(Cl)c1nnnn1Cc1ccccc1
Reaction time: 2 h

Procedure:
A stirred mixture of potassium 1-benzyl-1H-tetrazole-5-carboxylate (3.6 g; prepared as described in the specification of Belgian Pat. No. 845612), dry pyridine (0.75 ml) and dry toluene (65 ml) was cooled to 5° C. and treated with oxalyl chloride (12.5 ml). Stirring was maintained and the temperature was allowed to rise to 15° C. during a period of 2 hours. The mixture was filtered and the residue was washed with dry toluene. Evaporation of the combined toluene filtrate and washings, under diminished pressure, gave crude 1-benzyl-1H-tetrazole-5-carbonyl chloride in the form of an oil, which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]2[N:15](C(OC(C)(C)C)=O)[C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1.[N:31]1([C:35]([C:37]2[CH:38]=[C:39]([CH3:44])[C:40](Cl)=[N:41][CH:42]=2)=[O:36])[CH2:34][CH2:33][CH2:32]1.[H-].[Na+].[Cl-].[NH4+]>CS(C)=O>[N:31]1([C:35]([C:37]2[CH:38]=[C:39]([CH3:44])[C:40]([O:1][C:2]3[CH:3]=[C:4]([C:14]4[NH:15][C:16]([C:19]5[S:20][CH:21]=[CH:22][N:23]=5)=[CH:17][CH:18]=4)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=3)=[N:41][CH:42]=2)=[O:36])[CH2:34][CH2:33][CH2:32]1
Reactant: Cc1cc(C(=O)N2CCC2)cnc1Cl
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: COC[C@H](C)Oc1cc(Oc2ncc(C(=O)N3CCC3)cc2C)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 80 °C
Reaction time: 4.5 h
Yield: 72.3 %

Procedure:
t-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (59 mg, 0.137 mmol) synthesized in Example (38d) and 5-(azetidin-1-ylcarbonyl)-2-chloro-3-methylpyridine (45 mg, 0.232 mmol) synthesized in Example (61a) were dissolved in dimethyl sulfoxide (3.0 mL), and sodium hydride (60%, 25 mg, 0.63 mmol) was added, followed by stirring at 80° C. for 4.5 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, a saturated aqueous ammonium chloride solution (30 mL) was added, and extraction was carried out with ethyl acetate (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=60%-80%) to afford the desired compound (50 mg, yield 72%) as a yellow solid.
Reaction SMILES: [Na].Cl.[NH2:3][C:4]1[CH2:8][CH2:7][CH2:6][N:5]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=1.[N-]=C=O>CC(C)=O>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:3][C:4]2[CH2:8][CH2:7][CH2:6][N:5]=2)=[O:18])=[CH:12][CH:11]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NC1=NCCC1
Agent: Cl
Agent: [N-]=C=O
Agent: [Na]
Solvent: CC(C)=O
Product: O=C(NC1=NCCC1)Nc1ccc(Cl)cc1

Procedure:
Following a procedure similar to that described in Example 1 but using 15.3 g. sodium in 1900 ml. dry acetone, 80 g. 2-amino-1-pyrroline hydrochloride, and 102 g. 4-chlorophenyl isocyanate in 500 ml. dry acetone, except that ice-bath cooling was applied during the addition of the isocyanate, there was obtained after recrystallization from ethyl acetate 66 g. 1-(4-chlorophenyl)-3-(1-pyrrolin-2-yl)urea; m.p. 147°-150° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3]1.CCN(C(C)C)C(C)C.[C:17]([O:21][C:22]([NH:24][C:25]1([CH:31]([OH:35])[C:32](O)=[O:33])[CH2:28][C:27]([F:30])([F:29])[CH2:26]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:17]([O:21][C:22](=[O:23])[NH:24][C:25]1([CH:31]([OH:35])[C:32](=[O:33])[NH:7][C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)[CH2:28][C:27]([F:29])([F:30])[CH2:26]1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)NC1(C(O)C(=O)O)CC(F)(F)C1
Reactant: Cn1ccc(N)n1
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: Cn1ccc(NC(=O)C(O)C2(NC(=O)OC(C)(C)C)CC(F)(F)C2)n1
Reaction time: 2 h
Yield: 92 %

Procedure:
1-Methyl-1H-pyrazol-3-amine (158 mg, 1.63 mmol) and DIEA (1.08 mL, 6.52 mmol) was added to a solution of (1-tert-Butoxycarbonylamino-3,3-difluoro-cyclobutyl)-hydroxy-acetic acid (1.63 mmol) dissolved in DMF (20 mL). The solution was cooled to 0° C. and after 10 minutes HATU (620 mg, 1.63 mmol) was added. After approximately 2 hours at RT, LC-MS showed product and no starting material and the solvent was removed by rotary evaporation. The crude product was dissolved in 40 mL EtOAc and washed with 25 mL sat. NaHCO3 (aq). The organic phase was dried with Na2SO4, filtered and evaporated to dryness. The crude product was purified on a 25 g silica column on a Biotage Flashmaster, which gave the title product as a white solid (92%). TLC rf: 0.07 in heptane:ethyl acetate 1:1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:30]=[N:31][CH:32]=[C:33]([O:35][CH:36]([CH3:38])[CH3:37])[CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:30]=[N:31][CH:32]=[C:33]([O:35][CH:36]([CH3:38])[CH3:37])[CH:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: CC(C)Oc1cncc(Br)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cncc(OC(C)C)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 290, Step 1, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-5-isopropoxy-pyridine.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:3](=O)[O:2]1.[Br:12][C:13]1[CH:14]=[C:15]([CH2:20]C(O)=O)[CH:16]=[CH:17][C:18]=1[F:19].C([O-])(=O)C.[Na+]>>[Br:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][C:18]=1[F:19])[CH:20]=[C:3]1[C:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=2[C:1](=[O:11])[O:2]1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: O=C(O)Cc1ccc(F)c(Br)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: O=C1OC(=Cc2ccc(F)c(Br)c2)C2=C1CCCC2

Procedure:
4,5,6,7-tetrahydro-isobenzofuran-1,3-dione (7) (16.7 g, 109.7 mmol) and 3-bromo-4-fluorophenylacetic acid (15.0 g, 64.37 mmol) were heated in the presence of sodium acetate (0.259 g, 3.160 mmol) to 210° C. using a ‘Wood's Alloy’ bath for 4.5 hours. The reaction mixture was then poured into a crucible and cooled to give a crystalline solid. The solid was ground with a mortar and pestle and triturated with ethanol (20 ml). The resultant suspension was then filtered and washed with further ethanol (10 ml). The solid was then dried to afford the desired product as a mixture of geometric isomers. Main peak in LC-MS, (20.78 g, 94% purity) and required no further purification; m/z (LC-MS, ESP), RT=4.74 mins (no ionization observed).
Reaction SMILES: C([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([CH3:20])[C:12]2[N:21]=[CH:22][CH:23]=[CH:24][C:11]=2[C:10]1=[O:25])(=O)C1C=CC=CC=1.Cl>C(O)C>[CH3:20][N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:9][C:10](=[O:25])[C:11]2[CH:24]=[CH:23][CH:22]=[N:21][C:12]1=2
Reactant: CN1c2ccccc2N(C(=O)c2ccccc2)C(=O)c2cccnc21
Agent: Cl
Solvent: CCO
Product: CN1c2ccccc2NC(=O)c2cccnc21
Reaction time: 8 h

Procedure:
A mixture of 9.4 g (0.0285 mol) of the product obtained in step b, 150 ml ethanol and 5 ml concentrated aqueous hydrochloric acid was refluxed for five hours while stirring. The clear yellowish solution that had been formed was set aside overnight. The resulting precipitate was collected by filtration and thoroughly washed with diluted aqueous ammonia. The product was dried overnight in a stream of nitrogen at room temperature and thereafter was recrystallized from n-propanol. The colorless product had a m.p. of 235°-237° C. and was identified as 6,11-dihydro-11-methyl-5H-pyrido-[2,3-b][1,5]benzodiazepin-5-one. The yield was 3.3 g (51% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][Mg]Br>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([OH:9])([CH3:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: CC(C)(O)c1cccc(Cl)c1

Procedure:
This compound is prepared in a manner analogous to that of Step A of this Example, using 13.9 grams (0.09 mole) of methyl 3-chlorophenyl ketone and 33.3 mL of methylmagnesium bromide (3.0M in diethyl ether) in 50 mL of dry tetrahydrofuran, yielding 2-(3-chlorophenyl)propan-2-ol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[N+:18]([O-])=O)[CH:5]=1.Cl[Sn]Cl>>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[NH2:18])[CH:5]=1
Reactant: COC(=O)c1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Product: COC(=O)c1cccc(Oc2ccc(Cl)cc2N)c1
Yield: 95.4 %

Procedure:
The product from Example 208a (7.20 g, 23.40 mmol) was reduced with SnCl2 (13.310 g, 70.20 mmol) following the procedure from Example 1f to give the title compound (6.2 g, 95%).
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C@H:10]([OH:22])[C@@H:9]([CH2:23][O:24][Si:25]([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:8][C@H:5]1[S:6][CH3:7])=[N+:2]=[N-:3].[C:42]1([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:43]([C:48](Cl)=[O:49])=[CH:44][CH:45]=[CH:46][CH:47]=1>CN(C)C1C=CN=CC=1.ClCCCl>[N:1]([C@@H:4]1[C@@H:11]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[C@H:10]([O:22][C:48]([C:43]2[C:42]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:49])[C@@H:9]([CH2:23][O:24][Si:25]([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:8][C@H:5]1[S:6][CH3:7])=[N+:2]=[N-:3]
Reactant: COc1ccc(CO[C@H]2[C@H](O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O[C@@H](SC)[C@@H]2N=[N+]=[N-])cc1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: COc1ccc(CO[C@@H]2[C@@H](N=[N+]=[N-])[C@H](SC)O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@H]2OC(=O)c2ccccc2-c2ccccc2)cc1
Temperature: 25 °C
Yield: 76.5 %

Procedure:
A mixture of methyl 2-azido-6-O-tert-butyldiphenylsilyl-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D glucopyranoside (10) (12.7 g, 21.46 mmol), 4-dimethylaminopyridine (5.23 g, 42.92 mmol) in dry 1,2-dichloroethane (100 mL) was stirred at room temperature. Biphenylcarbonyl chloride (6.97 g, 32.19 mmol) was added to the stirred reaction mixture in 15 minutes. After the addition the resulting suspension was stirred under reflux for 3 hours. The reaction mixture was cooled to 10° C. and filtered. The crystalline solid was washed on the funnel with dry 1,2-dichloroethane (50 mL) and filtered. The filtrates were combined, diluted with CHCl3 (200 mL) and washed twice with diluted brine solution (water-brine 2:1) (150 mL). The organic layer was dried over MgSO4 and evaporated. The residue was crystallized from EtOH (75 mL) to give methyl 2-azido-6-O-tert-butyldiphenylsilyl-4-O-biphenylcarbonyl-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D-glucopyranoside (11) (12.7 g, 76%)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[O:12]C)=[CH:4][C:3]=1[O:14]C.B(Br)(Br)Br.[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[OH:12])=[CH:4][C:3]=1[OH:14]
Reactant: COc1cc2cccc(OC)c2cc1Cl
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Oc1cc2cccc(O)c2cc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
A 50 ml round bottom flask equipped with magnetic stirring bar was charged with solution of compound 47 (2.0 g, 9.0 mmol) in anhydrous CH2Cl2 (20 ml). Flask was filled in with argon atmosphere and BBr3 (9.0 g, 3.39 ml, 36.0 mmol) was added through a syringe over 5 min. Resultant mixture was magnetically stirred overnight at room temperature. Reaction mixture was carefully poured into ice-water mixture (30 g), diluted with CH2Cl2 and neutralized by addition of 2% NaOH (pH˜6-7). Organic phase was separated, washed with NaHCO3 (2×10 ml) and NaCl (20 ml) solutions, dried over MgSO4 and concentrated in vacuum to give desired product 48 (1.54 g, 7.9 mmol, 88% yield) as fluffy off-white solid. 1H NMR (DMSO-d6): δ 10.45 (s, 1H), 10.13 (s, 1H), 8.04 (s, 1H), 7.23-7.10 (m, 3H), 6.67 (d, J=7.3 Hz, 1H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH:27]=[CH:26][C:12]([C:13]([N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])=[CH:11][CH:10]=1)=[O:7])(O)=[O:2].P(C#N)(OCC)(OCC)=O.[CH2:38]([NH:40][CH2:41][CH3:42])[CH3:39]>CN(C)C=O.C(N(CC)CC)C>[CH2:38]([N:40]([CH2:41][CH3:42])[C:1]([CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])=[CH:26][CH:27]=1)=[O:7])=[O:2])[CH3:39]
Reactant: CCNCC
Reactant: O=C(O)CCC(=O)Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)CCC(=O)Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
1-[4-(3-Carboxypropionylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.5 g) is dissolved in dimethylformamide (1 ml) and thereto is added dropwise diethyl cyanophosphate (0.25 g) under ice-cooling. The mixture is stirred at room temperature for 30 minutes and then cooled again with ice. Thereto are added dropwise a solution of diethylamine (0.11 g) in dimethylformamide (1 ml) and triethylamine (0.34 g). The mixture is stirred at room temperature for 16 hours. The solvent is distilled off under reduced pressure and water is added to the resulting residue. The mixture is extracted with dichloromethane. The organic layer is washed successively with diluted hydrochloric acid, water, saturated sodium hydrogen carbonate solution, water and saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified by silica gel column chromatography (eluent; ethyl acetate), and recrystallized from n-hexane/ethyl acetate to give 1-[4-(3-diethylaminocarbonylpropionylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.42 g) as colorless scales, m.p. 165°-167° C.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8].[Cl:10][C:11]1[CH:19]=[CH:18][C:17]([SH:20])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].C(N(CC)CC)C.C(Cl)(Cl)Cl.CO>ClCCl>[Cl:10][C:11]1[CH:19]=[CH:18][C:17]([S:20][CH2:2][C:3]2[O:4][C:5](=[O:9])[O:6][C:7]=2[CH3:8])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: Cc1oc(=O)oc1CCl
Reactant: O=C(O)c1cc(S)ccc1Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1oc(=O)oc1CSc1ccc(Cl)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
In 80 ml of dichloromethane was dissolved 4.0 g of 4-chloromethyl-5-methyl-1,3-dioxol-2-one, and 5.1 g of 2-chloro-5-mercaptobenzoic acid (synthesized in accordance with the method described in Swiss Pat. No. 426,865, C.A. 68.P68728c (1968)] was added. Then, 5.6 g of triethylamine was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, the solvent was evaporated under reduced pressure, and the residue was subjected to medium-pressure silica gel column chromatography as in Example 1 [except that the column was prepared by using chloroform/methanol (10/1, v/v)]. Fractions of the main product obtained were concentrated to dryness under reduced pressure and the residue was dissolved in chroroform, and shaken with dilute hydrochloric acid. The chloroform layer was concentrated to dryness under reduced pressure, and then the residue was recrystallized from ethanol to give 4.8 g of the captioned compound as colorless crystals.
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].Cl.[C:8]1([NH:14][NH2:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(OC)=O.O>[C:8]1([NH:14][NH:15][CH:1]=[O:4])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: NNc1ccccc1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: COC=O
Product: O=CNNc1ccccc1
Reaction time: 12 h
Yield: 99.8 %

Procedure:
25 g of K2CO3 are added to a solution of 20 g of phenylhydrazine hydrochloride in 150 ml of methyl formate and 60 ml of water, and the mixture is refluxed for 1 hour and left at AT for 12 hours with stirring. The precipitate formed is filter-dried, and washed with a propan-2-ol/petroleum ether mixture. 18.8 g of the expected compound are obtained.
Reaction SMILES: CC(C)([O-])C.[Na+].[C:7]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=3)=[CH:17][CH:18]=2)[C@H:13]([NH2:31])[CH2:12][C@@H:11]1[CH3:32])(=[O:9])[CH3:8].Br[C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][N:35]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1>C1(C)C=CC=CC=1.CCOC(C)=O.C1CCCCC1>[C:7]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=3)=[CH:17][CH:18]=2)[C@H:13]([NH:31][C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][N:35]=2)[CH2:12][C@@H:11]1[CH3:32])(=[O:9])[CH3:8]
Reactant: CCOC(=O)c1ccc(-c2ccc3c(c2)[C@H](N)C[C@H](C)N3C(C)=O)cc1
Reactant: Cc1ccc(Br)nc1
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CCOC(=O)c1ccc(-c2ccc3c(c2)[C@H](Nc2ccc(C)cn2)C[C@H](C)N3C(C)=O)cc1
Temperature: 120 °C

Procedure:
Sodium tert-butoxide (135 mg, 1.41 mmol)) was added to a suspension of ethyl 4-((2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (for a preparation see Intermediate 16) (450 mg, 1.28 mmol), 2-bromo-5-methylpyridine (439 mg, 2.55 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (40 mg, 0.102 mmol) and tris(dibenzyldieneacetone)dipalladium(0) (47 mg, 0.051 mmol) in anhydrous toluene (4.5 mL). The mixture was heated under microwave irradiation to 120° C. for 1 h in a sealed vial. The mixture was partitioned between EtOAc and water, the aqueous layer was extracted twice with EtOAc, the combined organic phases were dried by passing through a hydrophobic frit and concentrated in vacuo to give a residue. The residue was purified by chromatography (10 g column, EtOAc/cyclohexane gradient followed by MeOH/EtOAc gradient) to give a residue. This residue was dissolved in a mixture of EtOAc (0.6 mL) and cyclohexane (0.4 mL). The solution was treated with cyclohexane (3 mL) to give an emulsion, which was allowed to stand at room temperature over a weekend. The solution was decanted from the precipitated dark brown oil and concentrated to dryness under a stream of nitrogen to give an oil. This oil was triturated with cyclohexane (2×3 mL), the residual gum isolated by decanting off the cyclohexane, dissolved in EtOAc and concentrated to dryness under a stream of nitrogen to give crude ethyl 4-((2S,4R)-1-acetyl-2-methyl-4-((5-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)benzoate as a pale brown foam (240 mg) which was used directly in the next step without further purification.