Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](S(O)(=O)=O)[C:5]2[CH:6]=[CH:7][C:8]([CH3:13])=[N:9][C:10]=2[C:11]=1[OH:12].C([O-])(O)=O.[Na+]>C(O)(=O)C.S(=O)(=O)(O)O.O>[Cl:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:13])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(S(=O)(=O)O)cc(Cl)c(O)c2n1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc2ccc(Cl)c(O)c2n1
Yield: 82.3 %

Procedure:
7-Chloro-8-hydroxy-2-methyl-quinoline-5-sulfonic acid (5.50 g, 20.09 mmol) was dissolved in acetic acid (30 ml) and sulfuric acid (3 ml), and the resulting solution was heated to 130° C. for 72 hours. Upon cooling, the reaction mixture was diluted with water (300 ml) and neutralized by the addition of solid NaHCO3. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via flash chromatography (gradient of hexane/EtOAc 95:5 to 70:30) to afford the title compound (3.20 g, 82%) as a yellow solid. 1H NMR (400 MHz, d6-DMSO): δ=10.6-10.1 (br, 1H), 8.30 (d, J=7.7 Hz, 1H), 7.55-7.51 (m, 2H), 7.43 (d, J=8.8 Hz, 1H), 2.77 (s, 3H). MS (ES−): 192.2 (M−H)−.
Reaction SMILES: CO[CH:3](OC)[C:4](=[N:7][OH:8])[C:5]#[N:6].[OH:11][CH2:12][CH2:13][NH:14][NH2:15].O.[S:17](=[O:21])(=[O:20])([OH:19])[OH:18]>CO>[S:17]([OH:21])([OH:20])(=[O:19])=[O:18].[NH2:6][C:5]1[N:14]([CH2:13][CH2:12][OH:11])[N:15]=[CH:3][C:4]=1[N:7]=[O:8]
Reactant: COC(OC)C(C#N)=NO
Reactant: NNCCO
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: Nc1c(N=O)cnn1CCO
Temperature: 66.5 °C
Yield: 88.1 %

Procedure:
To a flask having an inner volume of 25 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged 1.47 g (10.0 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile with a purity of 98.1% by weight synthesized in the same manner as in Example 1, 0.84 g (10.5 mmol) of 2-hydroxyethylhydrazine with a purity of 95% by weight, 0.54 ml of water, 10 ml of methanol and 1.18 g (12.0 mmol) of conc. sulfuric acid, and the mixture was reacted under reflux (66 to 67° C.) for 3 hours. After completion of the reaction, when the reaction mixture was analyzed by high performance liquid chromatography (absolute calibration curve method), it was found that 2.24 g of 5-amino-1-(2-hydroxyethyl)-4-nitrosopyrazole hydrogen sulfate (Reaction yield: 88.2%) had been formed.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:35]4[CH:36]=[N:37][C:38]([Cl:41])=[CH:39][CH:40]=4)([N:25]=CC4C=CC(OC)=CC=4)[C:19]4[N:20]([CH3:24])[CH:21]=[N:22][CH:23]=4)[CH:16]=3)[N:11]([CH2:42][CH:43]3[CH2:45][CH2:44]3)[C:10](=[O:46])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1COCC1>[NH2:25][C:18]([C:35]1[CH:36]=[N:37][C:38]([Cl:41])=[CH:39][CH:40]=1)([C:19]1[N:20]([CH3:24])[CH:21]=[N:22][CH:23]=1)[C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:42][CH:43]1[CH2:44][CH2:45]1)[C:10](=[O:46])[CH:9]=[C:8]2[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: COc1ccc(C=NC(c2ccc(Cl)nc2)(c2ccc3c(c2)c(-c2cccc(Cl)c2)cc(=O)n3CC2CC2)c2cncn2C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1cncc1C(N)(c1ccc(Cl)nc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2CC1CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.4 %

Procedure:
To a solution of the title compound of Example 45, the slower moving enantiomer of 4-(3-chloro-phenyl)-6-[(6-chloro-pyridin-3-yl)-[(4-methoxy-benzylidene)-amino]-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-1H-quinolin-2-one (141 g, 1.74 mmol) in THF (200 ml) was added 2N hydrochloric acid (20 ml) slowly. The reaction mixture was stirred at ambient temperature for 1.5 hour after which time it was cooled to 0° C. An aqueous solution of potassium carbonate was added followed by addition of ethyl acetate. After separation, the organic layer was washed with brine, dried over MgSO4 and concentrated under vacuum to give the crude product. It was chromatographed on silica gel with MeOH-CHCl3—NH4OH (1:99:0.1 to 2:98:0.1) as the eluents to afford the title compound as a white solid (0.844 g, 1.59 mmol, 90% yield). It is the faster eluting enantiomer of 6-[amino-(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-chloro-phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one with >99% optical purity.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.[CH3:13][S:14]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1)(=[O:16])=[O:15].FC(F)(F)C1C=C(Cl)C=CC=1C(O)C1C=CC=CC=1>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:21]([OH:22])[C:20]1[CH:19]=[CH:18][C:17]([S:14]([CH3:13])(=[O:16])=[O:15])=[CH:24][CH:23]=1
Reactant: FC(F)(F)c1ccccc1[Mg]Br
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Agent: OC(c1ccccc1)c1ccc(Cl)cc1C(F)(F)F
Product: CS(=O)(=O)c1ccc(C(O)c2ccccc2C(F)(F)F)cc1
Yield: 108.6 %

Procedure:
This material was prepared from 2-(trifluoromethyl)phenylmagnesium bromide (14.5 mmol) and 4-(methylsulfonyl)benzaldehyde (2.68 g, 13.8 mmol) using the procedure described for compound (96). The product was obtained as an amber gum (4.95 g, 100%).
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([C:10]([OH:12])=O)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:44]([O:47][C:48]1[C:57]([CH3:58])=[CH:56][C:51]([C:52]([NH:54][NH2:55])=[O:53])=[CH:50][C:49]=1[CH3:59])[CH:45]=[CH2:46]>C(Cl)Cl.CCOCC>[CH2:1]([C:5]1[S:9][C:8]([C:10]([NH:55][NH:54][C:52](=[O:53])[C:51]2[CH:50]=[C:49]([CH3:59])[C:48]([O:47][CH2:44][CH:45]=[CH2:46])=[C:57]([CH3:58])[CH:56]=2)=[O:12])=[CH:7][CH:6]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: C=CCOc1c(C)cc(C(=O)NN)cc1C
Reactant: CC(C)Cc1ccc(C(=O)O)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOc1c(C)cc(C(=O)NNC(=O)c2ccc(CC(C)C)s2)cc1C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
To a solution of 5-isobutyl-thiophene-2-carboxylic acid (830 mg, 4.51 mmol) and DIPEA (680 mg, 5.27 mmol) in DCM (20 mL) is added TBTU (1.59 g, 4.96 mmol) at rt. The mixture is stirred at rt for 45 min before 4-allyloxy-3,5-dimethyl-benzoic acid hydrazide (993 mg, 4.50 mmol) is added. Stirring is continued for 2 h. The mixture is diluted with ether (200 mL) and washed with 1M aq. HCl (3×50 mL), 1M aq. NaOH (3×50 mL) and brine (50 mL). The org. extract is dried over MgSO4, filtered and evaporated to give the crude 4-allyloxy-3,5-dimethyl-benzoic acid N′-(5-isobutyl-thiophene-2-carbonyl)-hydrazide (1.40 g) as a yellow oil that slowly solidifies; LC-MS: tR=1.02 min, [M+1]+=387.10.
Reaction SMILES: N1C=CC=NC=1.[CH3:7][C:8]1[N:12]2[CH2:13][CH2:14][NH:15][C:16](=[O:17])[C:11]2=[C:10]([CH3:18])[C:9]=1[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][C:33]([OH:35])=O)=[CH:28][CH:27]=2)[N:20]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:57][O:58][CH2:59][CH2:60][NH2:61]>C1COCC1.O>[CH3:7][C:8]1[N:12]2[CH2:13][CH2:14][NH:15][C:16](=[O:17])[C:11]2=[C:10]([CH3:18])[C:9]=1[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([CH2:32][C:33]([NH:61][CH2:60][CH2:59][O:58][CH3:57])=[O:35])=[CH:30][CH:31]=2)[N:20]=1
Reactant: COCCN
Reactant: Cc1c(-c2ccnc(Nc3ccc(CC(=O)O)cc3)n2)c(C)n2c1C(=O)NCC2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: c1cncnc1
Solvent: C1CCOC1
Solvent: O
Product: COCCNC(=O)Cc1ccc(Nc2nccc(-c3c(C)c4n(c3C)CCNC4=O)n2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of the pyrimidine acid Example I-70 {4-[4-(6,8-dimethyl-1-oxo-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-7-yl)-pyrimidin-2-ylamino]-phenyl}-acetic acid (0.05 g), EDCI (1.2 eq., 0.028 g) and HOBt (1.2 eq., 0.02 g) in THF (3 mL) was stirred at room temperature under nitrogen for 1 hour. 2-Methoxyethylamine (1.2 eq., 0.013 mL) was then added and the resulting reaction stirred at room temperature for 16 hours. Water (5 mL) was added and the solvent removed under vacuum to leave an aqueous suspension which was extracted with dichloromethane (2×2 mL). The combined organics were stripped to yield the crude product as a yellow oil (0.0656 g). Purification of the crude material (prep. HPLC) produced the title compound as a white solid (0.0269 g, 47%, with a purity of 98.37% by LCMS.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([C:27]([F:26])([F:37])[F:38])=[CH:29][CH:30]=2)[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(C(F)(F)F)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (110 mg, 0.44 mmol) and triethylamine (91 μL, 0.66 mmol) in methylene chloride (20 mL) was 4-(trifluoromethyl)benzoyl chloride (96 mg, 0.46 mmol) in methylene chloride (5 mL) added dropwise. After the addition the reaction was allowed to stir at ambient temperature for 15 min and was then washed with diluted aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:2) as the eluent. Yield: 150 mg (81%) of the title compound as white crystals: mp 203-204° C.; [α]21D−20° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 417 (10, M+).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11](C)[C:12]([O:20]C)=[C:13]([O:18]C)[CH:14]=2)[CH:9]1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[S:34][C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[CH:31]=2)=[CH:26][CH:25]=1)=O)(C)(C)C.B(Br)(Br)[Br:40]>ClCCl>[BrH:40].[S:34]1[C:30]([C:27]2[CH:28]=[CH:29][C:24]([CH2:23][CH:9]3[C:10]4[C:15](=[CH:14][C:13]([OH:18])=[C:12]([OH:20])[CH:11]=4)[CH2:16][CH2:17][NH:8]3)=[CH:25][CH:26]=2)=[CH:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]1=2
Reactant: BrB(Br)Br
Reactant: COc1cc2c(c(C)c1OC)C(Cc1ccc(-c3cc4ccccc4s3)cc1)N(C(=O)OC(C)(C)C)CC2
Solvent: ClCCl
Product: Br
Product: Oc1cc2c(cc1O)C(Cc1ccc(-c3cc4ccccc4s3)cc1)NCC2
Reaction time: 8 h

Procedure:
1-(4-Benzo[b]thiophen-2-yl-benzyl)-1,2,3,4-tetrahydro-isoquinoline-6,7-diol hydrobromide (22) was prepared as follows: To a stirred solution of 0.15 g (0.29 mmole) of 1-(4-benzo[b]thiophen-2-yl-benzyl)-6,7-dimethoxy-8-methyl-3,4-dihydro-1-H-isoquinoline-2-carboxylic acid tert-butyl ester in 10 ml of anhydrous dichloromethane under argon at −70° C., 0.9 ml (3 mol. equiv.) of 1M boron tribromide solution in n-hexanes was added. The stirred mixture was allowed to reach room temperature overnight and the solvents were evaporated under reduced pressure. The residue was dissolved in 10 ml of methanol and, again, the solvent was evaporated under reduced pressure. The solid residue was mixed with 10 ml of ether, separated on a glass filter funnel, washed with ether (3×20 ml) to afford an off-white solid, 130 mg (91%), mp 251-254° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[C:6](O)=[O:7])#[N:2].C1(C)C=CC=CC=1.S(Cl)([Cl:26])=O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([Cl:26])=[O:7])#[N:2]
Reactant: COc1c(C#N)cc(C(=O)O)cc1C(C)C
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1c(C#N)cc(C(=O)Cl)cc1C(C)C
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 3-cyano-5-isopropyl-4-methoxybenzoic acid (658 mg), toluene (7 mL), N,N-dimethylformamide (2 droplets) and thionyl chloride (0.33 mL) were added, and the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and then azeotroped with toluene to obtain the title compound (710 mg) as a brown oily substance.
Reaction SMILES: [N+]([O-])([O-])=[O:2].[Al+3:5].[N+]([O-])([O-])=[O:7].[N+]([O-])([O-])=[O:11].[Si:14]([O-:18])([O-:17])([O-:16])[O-:15].[Na+].[Na+].[Na+].[Na+].[Si]=O>>[OH-:2].[Al+3:5].[OH-:7].[OH-:11].[Si:14]([OH:18])([OH:17])([OH:16])[OH:15]
Reactant: O=[N+]([O-])[O-]
Reactant: [O-][Si]([O-])([O-])[O-]
Agent: O=[Si]
Agent: [Al+3]
Agent: [Na+]
Product: O[Si](O)(O)O
Product: [OH-]

Procedure:
An aqueous 6% aluminum nitrate solution containing 324 g of aluminum nitrate, Al(NO3)3.9H2O and an aqueous 15% sodium silicate solution containing 356 g of silicon oxide were mixed together to form a slurry of aluminum hydroxide and silicic acid gel. The resulting slurry mixture was washed with water until there was no soluble salt contained therein, and dried at 110°C under aeration. 400 Grams of the thus obtained pellets having a ratio of silica to alumina of 89:11 by weight and having particle sizes of 3 mm was immersed in 800 g of an aqueous 5% ammonium iodide solution at room temperature, for example, 25° to 30°C, for 4 days, then thoroughly washed with water to remove iodine ions, and dried at 120°C. 500 ml of the thus prepared silica-alumina catalyst was filled in a tubular reactor, and a gas mixture consisting of 12 moles of formaldehyde, 12 moles of acetaldehyde and 26.4 moles of ammonia preheated to 200°C was passed through the tubular reactor for 3 hours (SV = 1,160 hr-1), while keeping the tubular reactor at 420°C. The reaction gas mixture passed through the catalyst layer was cooled, and subjected to condensation. The resulting condensate was dehydrated with caustic soda, and 492 g of the thus obtained oil was distilled and quantitatively determined by gas chromatograph. The yields of the thus obtained reaction products were 38.1% pyridine (2.74 moles), 25.9% 3-picoline (1.55 moles) and 3.3% 3,5-lutidine (0.17 mole) on the basis of the amount of carbon of the aldehyde used. After the completion of the reaction, the catalyst was regenerated by burning the carbons deposited on the catalyst with air at 560°C or less. The required regeneration time was 3 hours.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:16]Br)=[CH:11][C:10]=1[CH2:26][OH:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([O:35][C:36](=[O:50])[CH:37]=[CH:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][C:46]([NH2:49])([CH3:48])[CH3:47])[CH:40]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(OCC)C>[NH3:49].[CH2:28]([O:35][C:36](=[O:50])[CH:37]=[CH:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][C:46]([NH:49][CH2:16][C@@H:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:10]([CH2:26][OH:27])[CH:11]=2)[O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])([CH3:47])[CH3:48])[CH:40]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(N)Cc1cccc(C=CC(=O)OCc2ccccc2)c1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(CO)c1
Solvent: CCOCC
Product: CC(C)(Cc1cccc(C=CC(=O)OCc2ccccc2)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c(CO)c1
Product: N
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A mixture of [2-(benzyloxy)-5-((1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl) phenyl]methanol (Preparation 23) (800 mg, 1.77 mmol) and 3-[3-(2-amino-2-methyl-propyl)phenyl]-acrylic acid benzyl ester (preparation 142), (1.10 g, 3.55 mmol) was stirred at 90° C. for 18 hours. The reaction mixture was then cooled to room temperature, diluted with diethyl ether (40 mL) and stirred for 4 hours. The resulting precipitate was filtered off, washing though with diethyl ether, and the filtrate was concentrated in vacuo to give a brown oil. Purification of the oil by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia afforded the title compound in 25% yield, 300 mg. 1H NMR (400 MHz, CD3OD) δ: 7.78 (1H, d), 7.38 (16H, m), 6.95 (1H, m), 6.58 (1H, d), 5.25 (2H, s), 5.04 (2H, s), 4.78 (1H, m), 4.64 (2H, m), 2.80 (2H, m), 2.68 (2H, m), 1.14 (3H, s), 1.10 (3H, s), 0.78 (9H, s), −0.03 (3H, s), −0.21 (3H, s) ppm; LRMS ESI m/z 680 [M+H]+
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[S:12])SCC.[NH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([NH:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[S:12]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: CCSC(=S)Nc1ccccn1
Product: CC(C)(C)OC(=O)NCCCNC(=S)Nc1ccccn1
Yield: 89.7 %

Procedure:
In a similar manner to in Reference Example 58, ethyl 2-pyridyldithiocarbamate (1.98 g) and t-butyl 3-aminopropylcarbamate (1.74 g) were reacted and crystallized from n-hexane-diethyl ether to give the title compound (2.78 g).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH2:22])=[CH:18][CH:17]=1.[F:23][C:24]1[CH:25]=[C:26]([S:31](Cl)(=[O:33])=[O:32])[CH:27]=[C:28]([F:30])[CH:29]=1>>[F:30][C:28]1[CH:27]=[C:26]([S:31]([NH:1][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][C:8]([NH:22][CH2:21][C:19]2[O:20][C:16]([CH3:15])=[CH:17][CH:18]=2)=[N:9]3)(=[O:32])=[O:33])[CH:25]=[C:24]([F:23])[CH:29]=1
Reactant: Cc1ccc(CN)o1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Product: Cc1ccc(CNc2ccc3c(NS(=O)(=O)c4cc(F)cc(F)c4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=430.5 (M+H+), was prepared in accordance with the general method of example 58 from 5-nitro-2-chloroquinoline, 5-methyl-2-furanmethanamine and 3,5-difluorobenzenesulfonylchloride.
Reaction SMILES: OC1C=CC=CN=1.[C:8]([O:12][C:13](=[O:41])[NH:14][C@H:15]([C@@H:34]1[CH2:38][C@@H:37]([CH3:39])[C:36](=[O:40])[O:35]1)[CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[CH3:31])[CH2:19][C:18]1([CH3:33])[CH3:32])([CH3:11])([CH3:10])[CH3:9].O.[CH:43]1([NH2:49])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>>[C:8]([O:12][C:13](=[O:41])[NH:14][C@@H:15]([CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[CH3:31])[CH2:19][C:18]1([CH3:33])[CH3:32])[C@@H:34]([OH:35])[CH2:38][C@H:37]([C:36](=[O:40])[NH:49][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)[CH3:39])([CH3:10])([CH3:9])[CH3:11]
Reactant: Cc1ccc(F)cc1N1CC(C)(C)N(C[C@H](NC(=O)OC(C)(C)C)[C@@H]2C[C@@H](C)C(=O)O2)CC1=O
Reactant: NC1CCCCC1
Agent: Oc1ccccn1
Solvent: O
Product: Cc1ccc(F)cc1N1CC(C)(C)N(C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](C)C(=O)NC2CCCCC2)CC1=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
7.6 mg of 2-hydroxypyridine (0.08 mmol) was added to a solution of 190 mg of {(S)-2-[2,2-dimethyl-4-(5-fluoro-2-methylphenyl)-5-oxopiperazin-1-yl]-1-[(2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl]ethyl}carbamic acid t-butyl ester obtained in Example (101b) (0.4 mmol) in cyclohexylamine (1.5 ml), and the mixture was stirred at 80° C. for one hour. The reaction mixture was cooled and then water was added, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=20/1) to obtain 195 mg of the title compound (yield: 85%).
Reaction SMILES: [CH:1]1([C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[N:26]=[C:25]([NH2:27])[C:24]2[C:19](=[CH:20][C:21]([O:30][CH3:31])=[C:22]([O:28][CH3:29])[CH:23]=2)[N:18]=1>>[ClH:16].[NH2:27][C:25]1[C:24]2[C:19](=[CH:20][C:21]([O:30][CH3:31])=[C:22]([O:28][CH3:29])[CH:23]=2)[N:18]=[C:17]([N:13]2[CH2:12][CH2:11][N:10]([C:8]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)=[O:9])[CH2:15][CH2:14]2)[N:26]=1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: O=C(C1CCCCCC1)N1CCNCC1
Product: COc1cc2nc(N3CCN(C(=O)C4CCCCCC4)CC3)nc(N)c2cc1OC
Product: Cl

Procedure:
N-(Cycloheptylcarbonyl)piperazine (0.02 mole) and 2-chloro-4-amino-6,7-dimethoxyquinazoline (0.02 mole) are reacted according to the procedure of Example 7. Crystallization of the product from methanol-isopropanol provides analytically pure 4-amino-2-[4-(cycloheptylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline hydrochloride, m.p. 278°-279° C. (corr.).
Reaction SMILES: Cl[C:2]1[C:3]([F:21])=[CH:4][C:5]2[C:6]([CH:20]=1)=[N:7][C:8]1[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>N1C=CC=CC=1>[F:21][C:3]1[C:2]([N:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)=[CH:20][C:6]2=[N:7][C:8]3[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reactant: CN1CCNCC1
Solvent: c1ccncc1
Product: CN1CCN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C)CC1

Procedure:
7-Fluoro-1-methyl-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under conditions analogous to Reference Example 1 but starting from 5 g of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 16 g of 1-methylpiperazine in 50 cm3 of pyridine. After concentrating the reaction mixture under reduced pressure, 25 cm3 of acetic acid are added to the residue, which is suspended in 100 cm3 of water. A very small amount of insoluble matter is removed by filtration through diatomaceous silica for filtration. 200 cm3 of 3N aqueous potassium hydroxide solution are added to the filtrate and a very small amount of insoluble matter is again removed by filtration through diatomaceous silica for filtration. 5 cm3 of acetic acid are added to the filtrate. The precipitate formed is drained and washed with 3 times 50 cm3 of water. After recrystallizing twice from 17 cm3 of dimethylformamide each time, 3.2 g of 7-fluoro-1-methyl-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid melting at 356° C.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I.CS[C:19]1[NH:20][CH2:21][CH2:22][CH2:23][N:24]=1.[ClH:25]>CO>[ClH:25].[C:10]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][NH:9][C:19]2[NH:24][CH2:23][CH2:22][CH2:21][N:20]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CSC1=NCCCN1
Reactant: NCC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: I
Solvent: CO
Product: c1ccc(C(CNC2=NCCCN2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A flask containing a mixture of 2,2-diphenylethylamine (5.92 g; 3.00×10-2 mole) and 2-methylthio-1,4,5,6-tetrahydropyrimidine hydroiodide (7.74 g, 3.00×10-2 mole) was immersed in an oil bath which had been preheated to ca. 155° C. The reaction was stirred at between 150°-168° C. for 1.5 hours. The resulting yellow glass was dissolved in methanol. The methanol was evaporated and the resulting yellow oil was dissolved in dichloromethane. This solution was transferred to a separatory funnel where it was washed with 2N aqueous NaOH and saturated aqueous NaCl. After drying over anhydrous Na2SO4, the dichloromethane was evaporated giving a foam which was dissolved in methanol (125 ml). This solution was cooled to 0° C. at which time it was treated with a methanolic solution of HCl. After 10-15 minutes most of the methanol was evaporated and 2-butanone was added. After several days the crystals were collected by filtration. Recrystallization from isopropanol afforded 2-(2,2-diphenylethylamino)-1,4,5,6-tetrahydropyrimidine hydrochloride as off-white crystals: 3.80 g (40%), m.p. 180°-182° C.