Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[S:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[S-:13][C:14]#[N:15].[K+].BrBr.C>C(O)(=O)C>[F:12][C:2]([F:11])([F:1])[S:3][C:4]1[CH:10]=[CH:9][C:7]2[N:8]=[C:14]([NH2:15])[S:13][C:6]=2[CH:5]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(SC(F)(F)F)cc1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(SC(F)(F)F)cc2s1
Temperature: 10 °C
Yield: 58.1 %

Procedure:
The procedure is as in Example 1, starting with 4-trifluoromethylthioaniline (3.85 g), potassium thiocyanate (7 g) and bromine (1 cc) in acetic acid (30 cc). The light brown crude product is taken up with acetic acid (250 cc) at 80° C. and the solution obtained is treated with decolorizing charcoal (0.4 g) and filtered; the filtrate is cooled to about 10° C., diluted with water (150 cc) and alkalinized with 28% strength ammonia solution (400 cc). The precipitate obtained is drained, dried in the air and recrystallized in a mixture of cyclohexane (250 cc) and isopropyl ether (30 cc). 6-Trifluoromethylthio-2-benzothiazolamine (2.9 g), m.p. 155° C., is obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:20]([CH:23]=O)=[CH:21][N:22]=2)[C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2.C(C=O)=O.N.[NH:30]1[CH:34]=[CH:33][N:32]=C1>CO>[NH:30]1[CH:34]=[CH:33][N:32]=[C:23]1[C:20]1[N:8]2[C:9]3[C:14]([N:15]=[C:6]([NH:5][CH2:4][CH2:3][CH2:2][OH:1])[C:7]2=[N:22][CH:21]=1)=[CH:13][C:12]([C:16]([F:18])([F:17])[F:19])=[CH:11][CH:10]=3
Reactant: O=Cc1cnc2c(NCCCO)nc3cc(C(F)(F)F)ccc3n12
Reactant: c1c[nH]cn1
Agent: N
Agent: O=CC=O
Solvent: CO
Product: OCCCNc1nc2cc(C(F)(F)F)ccc2n2c(-c3ncc[nH]3)cnc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
To a solution of 4-[(3-hydroxypropyl)amino]-7-(trifluoromethyl)imidazo[1,2-a]quinoxalin-1-carbaldehyde (35 mg, 0.10 mmol) in methanol (1.2 mL) was added glyoxal (40% in water, 15 μL, 0.10 mmol). The mixture was cooled at 0° C. and NH3 (2M in ethanol, 150 μL, 0.30 mmol) was added. The reaction was stirred at 25° C. under argon overnight. The reaction was followed by TLC that showed small conversion of the starting material in imidazole. The addition of reactants was repeated 4 times in 4 days, until the TLC indicated completion of the reaction. The reaction was concentrated. The crude product was purified twice by preparative TLC (dichloromethane/methanol 9/1) to give the title compound (7 mg, 18%) as a beige powder.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].C(N(CC)CC)C.[CH3:15][C@@:16]12[C@H:26]3[C@@H:27]([OH:40])[CH2:28][C@:29]4([CH3:39])[C@@:33]([OH:38])([C:34]([CH2:36][OH:37])=[O:35])[CH2:32][CH2:31][C@H:30]4[C@@H:25]3[CH2:24][CH2:23][C:22]1=[CH:21][C:19](=[O:20])[CH2:18][CH2:17]2>C(Cl)(Cl)Cl>[CH3:15][C@@:16]12[C@H:26]3[C@@H:27]([OH:40])[CH2:28][C@:29]4([CH3:39])[C@@:33]([OH:38])([C:34]([CH2:36][OH:37])=[O:35])[CH2:32][CH2:31][C@H:30]4[C@@H:25]3[CH2:24][CH2:23][C:22]1=[CH:21][C:19](=[O:20])[CH2:18][CH2:17]2.[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([O-:6])=[O:20]
Reactant: O=C(Cl)CCCCl
Agent: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C([O-])CCCCl
Reaction time: 72 h

Procedure:
4 portions of 4-chlorobutanoylchloride (0.32 ml×4) and triethylamine (0.3 g×4) were added in 24 hours to a solution of hydrocortisone (1 g) in CHCl3 dried over P2O5, and stirred for 3 days. The solution was treated with water, the organic phase was separated, dried (Na2SO4) and deprived of the solvent at reduced pressure. The crude residue was ground with hexane and CH2Cl2 to give a white solid with a 53% yield by weight, which had a melting point (m.p.) of 155° C.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:19][CH:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][C:27]=4[C:32]([O:34][CH3:35])=[O:33])[CH2:22][CH2:21]3)=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH3:35][O:34][C:32]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:26]=1[N:23]1[CH2:22][CH2:21][CH:20]([CH2:19][O:18][C:12]2[CH:11]=[C:10]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9]3)=[CH:14][CH:13]=2)[CH2:25][CH2:24]1)=[O:33]
Reactant: COC(=O)c1cnccc1N1CCC(COc2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3)CC1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cnccc1N1CCC(COc2ccc3c(c2)CNCC3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.4 %

Procedure:
To a solution of 7-[1-(3-methoxycarbonylpyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (37 mg) in chloroform (0.5 ml) was added trifluoroacetic acid (0.15 ml), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was evaporated. To the obtained residue was added aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and dried under reduced pressure to give the title compound (30 mg).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[F:21].C(O[B:26]1[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]1)(C)C>C1COCC1.CCOCC>[F:13][C:14]1[C:15]([F:21])=[C:16]([CH3:20])[CH:17]=[CH:18][C:19]=1[B:26]1[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]1
Reactant: Cc1cccc(F)c1F
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1F
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 50.5 %

Procedure:
A 2.5 M solution of n-butyllithium (3.4 mL, 8.5 mmol) was added to a stirred solution of diisopropylamine (1.2 mL, 8.5 mmol) in THF (25 mL) at −20° C. The resulting solution was stirred at −20° C. for 10 minutes, then cooled to −78° C. A solution of 1,2-difluoro-3-methylbenzene (1.0 g, 7.8 mmol) in THF was added dropwise and stirred at −78° C. for 2 h. 2-Isopropoxy-4,4,5,5-tetramethyl[1,3,2]dioxaborolane (1.6 g, 8.6 mmol) in THF was then added and the brown solution was slowly warmed to 23° C. over 16 hours. The reaction mixture was then added to ether and extracted with water and with 0.1N sodium hydroxide. The combined aqueous extracts were acidified with concentrated HCl then extracted with dichloromethane. The organic phase was dried and concentrated to give the title compound (1.0 g, 50% yield): 1H NMR (CDCl3): δ 7.32 (m, 1H), 6.92 (m, 1H), 2.31 (s, 3H), 1.32 (s, 12H).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[Cl:14]>O>[Cl:14][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:6]=1[N:5]=[C:1]=[S:2])[C:10]#[N:11]
Reactant: S=C(Cl)Cl
Reactant: N#Cc1ccc(N)c(Cl)c1
Solvent: O
Product: N#Cc1ccc(N=C=S)c(Cl)c1

Procedure:
To a suspension of thiophosgene (2 mL) in water (5 mL) was added 4-amino-3-chloro-benzonitrile (1 g, 7 mmol) in small portions over a period of 1 h at 25° C. The mixture was extracted with ethyl acetate (3×25 mL). Combined organic phase was washed with brine (1×50 mL), dried (MgSO4) and concentrated to dryness in vacuo. The title compound 3d was obtained as a tan solid (1.3 g, 96% yield).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:27][C:28]([N:30]1[CH2:35][CH2:34][CH2:33][C@@H:32]([C:36]2[N:40]([CH2:41][CH2:42][CH2:43][O:44][CH3:45])[C:39]3[CH:46]=[CH:47][CH:48]=[CH:49][C:38]=3[N:37]=2)[CH2:31]1)=[O:29])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=O)(C)(C)C.[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53]>C(Cl)Cl.CO.CC#N.O>[NH2:8][C@@H:9]([CH2:27][C:28]([N:30]1[CH2:35][CH2:34][CH2:33][C@@H:32]([C:36]2[N:40]([CH2:41][CH2:42][CH2:43][O:44][CH3:45])[C:39]3[CH:46]=[CH:47][CH:48]=[CH:49][C:38]=3[N:37]=2)[CH2:31]1)=[O:29])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53]
Reactant: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc(-c4ccc(C(=O)OC)cc4)cc3)NC(=O)OC(C)(C)C)C2)nc2ccccc21
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@H](N)Cc3ccc(-c4ccc(C(=O)OC)cc4)cc3)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 4′-((R)-2-(tert-butoxycarbonylamino)-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutyl)biphenyl-4-carboxylate (53A) (0.08 mmol, 0.054 g) was weighed into a 20 mL scintillation vial and dissolved in CH2Cl2 (2 mL). Trifluoroacetic acid (2 mL) was then added and the solution was stirred at room temperature for 2 hrs. The solvent was removed in-vacuo affording a clear colored oil. This oil was re-dissolved in methanol (3 mL), filtered, and then purified by preparative LC/MS (20-55% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording a clear colored oil. This oil was re-dissolved in CH3CN (1 mL) and water (2 mL). The resultant solution was frozen and lyophilized to afford methyl 4′-((R)-2-amino-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutyl)biphenyl-4-carboxylate (123) as its trifluoroacetic acid salt and as a white flocculent solid. (0.07 mmol, 0.040 g, 88% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.40-1.63 (m, 1H) 1.73-2.21 (m, 5H) 2.56-2.87 (m, 3H) 2.91-3.15 (m, 3H) 3.16-3.52 (m, 5H) 3.68-3.92 (m, 4H) 4.05-4.70 (m, 5H) 7.37-7.53 (m, 4H) 7.68-7.87 (m, 6H) 8.02-8.07 (m, 2H). ESI-MS: 569.3 m/z (M+H)+.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC1(C)C(C)(C)OB([C:51]2[NH:59][C:58]3[CH2:57][CH2:56][NH:55][C:54](=[O:60])[C:53]=3[CH:52]=2)O1.Br[C:63]1[CH:64]=[CH:65][CH:66]=[C:67]2[C:72]=1[N:71]=[C:70]([NH:73][CH:74]([CH3:76])[CH3:75])[N:69]([C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1)[C:68]2=[O:83]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:74]([NH:73][C:70]1[N:69]([C:77]2[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=2)[C:68](=[O:83])[C:67]2[C:72](=[C:63]([C:51]3[NH:59][C:58]4[CH2:57][CH2:56][NH:55][C:54](=[O:60])[C:53]=4[CH:52]=3)[CH:64]=[CH:65][CH:66]=2)[N:71]=1)([CH3:76])[CH3:75]
Reactant: CC(C)Nc1nc2c(Br)cccc2c(=O)n1-c1ccccc1
Reactant: CC1(C)OB(c2cc3c([nH]2)CCNC3=O)OC1(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)Nc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2c(=O)n1-c1ccccc1
Temperature: 80 °C
Yield: 43.8 %

Procedure:
Argon was bubbled into a mixture of potassium phosphate tribasic (0.26 g, 1.22 mmol), Xphos (Strem; 0.015 g, 0.030 mmol), Pd2dba3 (Strem; 0.014 g, 0.015 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (609) (0.32 g, 1.22 mmol), 8-bromo-2-(isopropylamino)-3-phenylquinazolin-4(3H)-one (402c, 0.109 g, 0.304 mmol) in 2 mL dioxane and 0.4 mL water for 2 min. The reaction was sealed and heated to 80° C. After 2 h the reaction was concentrated onto 1.5 g silica gel and dried. The material was purified by silica gel chromatography (24 g column) using 0-100% 90/10 DCM/MeOH in DCM. The product-containing fractions were concentrated to afford 2-(isopropylamino)-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-3-phenylquinazolin-4(3H)-one (55 mg, 0.133 mmol, 43.7% yield) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.15 (1H, br. s.), 8.03 (1H, dd, J=7.7, 1.5 Hz), 7.78 (1H, dd, J=7.7, 1.5 Hz), 7.52-7.66 (3H, m), 7.35-7.46 (2H, m), 7.17 (1H, t, J=7.7 Hz), 7.07 (1H, d, J=2.0 Hz), 6.94 (1H, s), 5.25 (1H, d, J=7.2 Hz), 4.13-4.28 (1H, m), 3.42 (2H, td, J=6.8, 2.3 Hz), 2.86 (2H, t, J=6.8 Hz), 1.20 (6H, d, J=6.5 Hz). m/z (ESI, +ve) 414.1 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].C(O)CC.[CH2:17]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:18]1[O:20][CH2:19]1.[ClH:34]>O>[ClH:34].[OH:20][CH:18]([CH2:17][O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:19][NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9]
Reactant: CCCCCCCCCCCCOCC1CO1
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: Cl
Solvent: CCCO
Solvent: O
Product: CCCCCCCCCCCCOCC(O)CN[C@@H](CCCNC(=N)N)C(=O)O
Reaction time: 0.5 h
Yield: 33108.2 %

Procedure:
L-arginine (17.4 g, 0.1 mmols) were dissolved in 100 ml of water in a three-necked round flask, and 100 ml of propanol were added thereto. Dodecyl glycidyl ether [made by Sakamoto Yakuhin Kogyo Co., Ltd., 24.2 g (0.1 mols)] was added thereto dropwise over a period of 30 minutes while being heat-stirred under reflux, and the mixture was stirred as such under reflux, for 3 hours. After it was identified through TLC and gas chromatography that dodecyl glycidyl ether disappeared, the residue was neutralized with 10.1 g (0.1 mols) of 36-% hydrochloric acid. The reaction solution was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (Kieselgel 60 made by Merck & Co., Inc., eluent--mixture of chloroform, methanol and acetic acid at a ratio of 3:1:0.5) to give 15.0 g of N-(2-hydroxy-3-dodecyloxypropyl)-L-arginine hydrochloride in a yield of 36.0%.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([OH:15])=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.[ClH:17].[Cl:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[OH-].[K+]>C1(C)C=CC=CC=1.O>[ClH:18].[ClH:17].[N:22]1([CH2:21][CH2:20][CH2:19][O:1][C:2]2[CH:14]=[CH:13][C:12]3[C:11]4[C:6](=[CH:7][C:8]([O:15][CH2:19][CH2:20][CH2:21][N:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)=[CH:9][CH:10]=4)[C:5](=[O:16])[C:4]=3[CH:3]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: ClCCCN1CCCCC1
Reactant: O=C1c2cc(O)ccc2-c2ccc(O)cc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1c2cc(OCCCN3CCCCC3)ccc2-c2ccc(OCCCN3CCCCC3)cc21
Reaction time: 20 h

Procedure:
A mixture of 63.6 g (0.30 mole) of 2,7-dihydroxy-fluoren-9-one, 188 g (0.95 mole) of 1-(3-chloropropyl) piperidine hydrochloride, 132 g (2.0 mole) of 85% potassium hydroxide in 900 ml of toluene and 300 ml of water is refluxed with vigorous stirring for 20 hours. The layers are separated upon cooling and the organic layer is washed 3 times with water, once with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. The mixture is filtered and the solvent removed in vacuo. The residue is taken up in isopropyl alcohol and acidified to Congo Red with ethereal hydrogen chloride. The solid which precipitates is filtered, recrystallized from a mixture of 3 parts isopropyl alcohol to 1 part methanol, and the 2,7-bis(3-piperidinopropoxy)fluoren-9-one dihydrochloride so prepared is dried at 100° C. for 24 hours under vacuum, m.p. 279.5°-80.5° C., λmaxH2O 270, and E1cm1% 1370.
Reaction SMILES: [N:1]1([C:51](OC(C)(C)C)=O)[CH2:50][CH2:49][CH2:48][C@H:2]1[C:3]([NH:5][C@@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][CH2:28][C:29]([NH:31][C@H:32]([C:37]([NH:39][C@H:40]([C:45]([NH2:47])=[O:46])[CH2:41][CH2:42][S:43][CH3:44])=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].Cl>C(O)(=O)C>[NH:1]1[CH2:51][CH2:50][CH2:49][CH2:48][C@H:2]1[C:3]([NH:5][C@@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][CH2:28][C:29]([NH:31][C@H:32]([C:37]([NH:39][C@H:40]([C:45]([NH2:47])=[O:46])[CH2:41][CH2:42][S:43][CH3:44])=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Agent: Cl
Solvent: CC(=O)O
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@@H]1CCCCN1)C(N)=O

Procedure:
Condensation of BocPro-DPhe-PheNHNH2 (1.98 g.) and HGly-Leu-MetNH2 hydrochloride salt (Example 7, 1.3 g.) by the acyl azide method (Yajima et al., Chem. Pharm. Bull., vol. 19, p. 1900, 1971) gave BocPro-DPhe-Phe-Gly-Leu-MetNH2 in 82% yield. De-t-butoxycarbonylation of BocPro-DPhe-Phe-Gly-Leu-MetNH2 (1.8 g.) using hydrogen chloride in acetic acid gave HPro-DPhe-Phe-Gly-Leu-MetNH2, which was isolated as the amorphous white solid phosphate (1:1) salt monohydrate in 59% yield.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13]([NH:15][C:16]([N:18]3[CH:22]=[CH:21]N=C3)=[O:17])=[N:12][C:11]=2[CH3:23])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.NCC[C:34]([NH:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].O>CN(C)C=O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:14][C:13]([NH:15][C:16](=[O:17])[NH:18][CH2:22][CH2:21][C:34]([NH:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[N:12][C:11]=2[CH3:23])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(-c2sc(NC(=O)n3ccnc3)nc2C)cc1
Reactant: CC(C)(C)NC(=O)CCN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc(-c2sc(NC(=O)NCCC(=O)NC(C)(C)C)nc2C)cc1
Reaction time: 1.5 h

Procedure:
Imidazole-1-carboxylic acid [5-(4-acetyl-phenyl)-4-methyl-thiazol-2-yl]-amide (0.455 g, 1.40 mmol) is dissolved in dimethylformamide (10 ml) and treated with triethylamine (0.21 ml, 1.47 mmol) and 3-Amino-N-tert-butyl-propionamide (0.266 g, 1.47 mmol). The reaction mixture is stirred for 1.5 hours, then water (200 ml) added and the resulting suspension filtered. The solid is washed with water and dried under high vacuum to afford the titled product as a pale yellow solid. [M+H] 403.34
Reaction SMILES: OC(CO)CCCCOC1C=CC(OC)=CC=1.[C:18]([O:25][CH2:26][CH:27]1[CH2:31][O:30]C(C)(C)[O:28]1)(=[O:24])[CH2:19][CH2:20][C:21]([CH3:23])=[O:22]>>[C:18]([O:25][CH2:26][CH:27]([OH:28])[CH2:31][OH:30])(=[O:24])[CH2:19][CH2:20][C:21]([CH3:23])=[O:22]
Reactant: CC(=O)CCC(=O)OCC1COC(C)(C)O1
Agent: COc1ccc(OCCCCC(O)CO)cc1
Product: CC(=O)CCC(=O)OCC(O)CO

Procedure:
Synthesis in analogy to 1c from (2,2-dimethyl-1,3-dioxolan-4-yl)methyl levulinate (27a);
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.C(C1C=CC=CC=1)(=O)C1C=CC=CC=1.[OH-].[K+].Cl>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Cc1cccc(C2CC2)c1O
Reactant: Oc1cc(Cl)nnc1Cl
Agent: Cl
Agent: O=C(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CO
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 62 %

Procedure:
To a mixture of 305 mg (purity: 99.0%; 1.83 mmol) of 4-hydroxy-3,6-dichloropyridazine and 846 mg (5.62 mmol) of 2-cyclopropyl-6-methylphenol were added benzophenone (2.76 g) and 327 mg (5.55 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 314 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 62%) and 3.2 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.6%) were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12](=[O:14])(=[O:13])[C:11]3[CH:15]=[C:16]([C:19](O)=[O:20])[CH:17]=[CH:18][C:10]=3[CH:9]=[CH:8][C:7]=2[CH:22]=1.C1C2C=CC3C=CC=CC=3S(=O)(=O)C=2C=C(C(O)=O)C=1>>[OH:20][CH2:19][C:16]1[CH:17]=[CH:18][C:10]2[CH:9]=[CH:8][C:7]3[CH:22]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[S:12](=[O:14])(=[O:13])[C:11]=2[CH:15]=1
Reactant: COc1ccc2c(c1)C=Cc1ccc(C(=O)O)cc1S2(=O)=O
Agent: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccccc1C=C2
Product: COc1ccc2c(c1)C=Cc1ccc(CO)cc1S2(=O)=O

Procedure:
Repeat the process of Example 6, substituting an equivalent quantity of 8-methoxy-dibenzo[b,f]thiepin-3-carboxylic acid 5,5-dioxide for the dibenzo[b,f]thiepin3-carboxylic acid 5,5-dioxide, to obtain the title product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=[O:22])/[CH:10]=[C:11]1\[S:12][C:13]([CH3:21])=[C:14]([CH3:20])[N:15]\1[CH2:16][CH2:17][CH2:18][CH3:19].C([O-])(O)=O.[Na+].Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>CCOC(C)=O.O>[CH2:16]([N:15]1[C:14]([CH3:20])=[C:13]([CH3:21])[S:12]/[C:11]/1=[CH:10]\[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][C:29](=[O:30])[O:31][CH2:32][CH3:33])=[O:22])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCN1C(C)=C(C)S/C1=C\C(=O)c1cc(Cl)ccc1N
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)c1cc(Cl)ccc1NC(=O)OCC
Yield: 97.8 %

Procedure:
To a solution of Example 139 (17 mg, 0.05 mmol) and NaHCO3 (42 mg, 0.5 mmol) in EtOAc (5 mL) and H2O (5 mL) was added dropwise at room temperature a solution of ethyl chloroformate (0.06 mL, 0.06 mmol) in EtOAc (3 mL) and the reaction was continued for the next 4 h. The ethyl acetate layer was separated, washed with brine, dried with anhydrous MgSO4 and concentrated under reduced pressure. The residue was chromatographed (EtOAc as eluent) to afford 20 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 0.94 (t, J=7 Hz, 3H), 1.24 (t, J=7 Hz, 3H), 1.37 (sextet, J=7 Hz, 2H), 1.62 (quintet, J=7 Hz, 2H), 2.10 (s, 3H), 2.14 (s, 3H), 4.13 (m, 4H), 6.56 (s, 1H), 7.42 (dd, J=9 Hz, 3 Hz, 1H), 7.96 (d, J=3 Hz, 1H 8.23 (d, J=9 Hz, 1H), 11.98 (s, 1H); MS (DCI/NH3) m/z 409 (M+H)+. Anal calcd for C20H25ClN2O3S: C, 58.74; H, 6.16; N, 6.85. Found: C, 59.02; H, 5.98; N, 6.31.
Reaction SMILES: [N:1]1([C:6]([CH:8]2[C:13]3[N:14]=[CH:15][NH:16][C:12]=3[CH2:11][CH2:10][NH:9]2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCOCC1>[N:1]1([CH2:6][CH:8]2[C:13]3[N:14]=[CH:15][NH:16][C:12]=3[CH2:11][CH2:10][NH:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(C1NCCc2[nH]cnc21)N1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: c1nc2c([nH]1)CCNC2CN1CCCC1

Procedure:
3.63 g (16.48 mmoles) of 4-(pyrrolidin-1-yl)carbonyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine were added portionwise, at room temperature, under nitrogen atmosphere, to a slurry of 1.00 g (26.32 mmoles) of lithium aluminium hydride in 180 ml of dry dioxane.
Reaction SMILES: C[C:2]([C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[C:6]([F:12])[CH:5]=1)=[O:3].[PH2]([O-])=[O:14].[Na+]>>[Cl:10][C:9]1[CH:8]=[C:7]([Cl:11])[C:6]([F:12])=[CH:5][C:4]=1[C:2]([OH:3])=[O:14]
Reactant: CC(=O)c1cc(F)c(Cl)cc1Cl
Reactant: O=[PH2][O-]
Agent: [Na+]
Product: O=C(O)c1cc(F)c(Cl)cc1Cl

Procedure:
Namely, 2,4-dichloro-5-fluoroacetophenone is subjected to a haloform reaction in a 12% sodium hypophosphite aqueous solution to obtain 2,4-dichloro-5-fluorobenzoic acid. Then, this benzoic acid is reacted with an alcohol or with a phenol in the presence of an acid catalyst to obtain the above-mentioned fluorine-containing benzoate.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][CH:6]=1.Cl.[NH2:20][OH:21].O>C(O)C>[NH2:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[N:20][OH:21])[CH3:12])=[CH:7][CH:6]=1
Reactant: NO
Reactant: CC(=O)c1ccc(Oc2ccc(Cl)cc2N)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(=NO)c1ccc(Oc2ccc(Cl)cc2N)cc1
Temperature: 60 °C
Yield: 41.2 %

Procedure:
To the product from Example 163a (150 mg, 0.57 mmol) in ethanol (15 mL) was added hydroxylamine hydrochloride (41.8 mg, 0.60 mmol), and disopropylethylamine (82 mg, 0.63 mmol). The reaction was heated at 60° C. for 3 h. The reaction was cooled and poured into water. The solution was extracted with ethyl ether. The organic layer washed with water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the title compound (65 mg, 42%).