Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:9]2[CH:10]=[CH:11][O:12][C:8]=2[C:7]([NH:13][S:14]([C:17]2([CH2:20][CH:21]=[O:22])[CH2:19][CH2:18]2)(=[O:16])=[O:15])=[C:6]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])[C:5]=1[F:32].CO.C(OCC)(=O)C>C1COCC1.CCCCCC>[F:3][C:4]1[C:9]2[CH:10]=[CH:11][O:12][C:8]=2[C:7]([NH:13][S:14]([C:17]2([CH2:20][CH2:21][OH:22])[CH2:19][CH2:18]2)(=[O:15])=[O:16])=[C:6]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])[C:5]=1[F:32]
Reactant: O=CCC1(S(=O)(=O)Nc2c(Nc3ccc(I)cc3F)c(F)c(F)c3ccoc23)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=S(=O)(Nc1c(Nc2ccc(I)cc2F)c(F)c(F)c2ccoc12)C1(CCO)CC1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
NaBH4 (0.117 g, 0.82 mmol) was added to a solution of 1-(2-oxo-ethyl)-cyclopropanesulfonic acid [4,5-difluoro-6-(2-fluoro-4-iodo-phenylamino)-benzofuran-7-yl]-amide (0.086 g, 0.1557 mmol) in dry THF (10 mL) at 0° C. This was followed by the addition of methanol (2 mL) dropwise over a period of 10 minutes at 0° C. The reaction mass was stirred for 30 minutes at 10° C. The reaction was monitored by TLC (60% ethyl acetate in hexane). The reaction mass was partitioned between ethyl acetate (50 mL) and water. The organic layer was washed with water, brine solution and concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (60% ethyl acetate in hexane) afforded 0.040 g of the product (46% yield). 1H NMR (DMSO-d6, 300 MHz): δ 9.56 (bs, 1H), 8.34 (d, 1H), 7.77 (bs, 1H), 7.56 (dd, 1H), 7.48 (d, 1H), 7.22 (d, 1H), 6.48-6.52 (m, 1H), 4.52 (bs, 1H), 3.51 (t, 2H), 2.20 (t, 2H), 0.85 (t, 2H), 0.55 (t, 2H). LCMS: 100%, m/z=550.8 (M−1). HPLC: 96.79%
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18](=[O:26])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[O:27]C)[N:11]=1)[CH3:9])(C)(C)C.B(Br)(Br)Br.CO>C(Cl)Cl>[NH2:7][C@H:8]([C:10]1[N:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:18](=[O:26])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[OH:27])[N:11]=1)[CH3:9]
Reactant: COc1cccc2nc([C@H](C)NC(=O)OC(C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: C[C@H](N)c1nc2cccc(O)c2c(=O)n1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of (S)-tert-butyl(1-(5-methoxy-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate (100 mg, 0.25 mmol) in DCM (3 mL) at −78° C. was added BBr3 (1M/DCM, 0.63 mL, 0.63 mmol). The reaction was stirred at −78° C. for 20 min, then warmed to ambient temperature. After stirring 10 minutes at ambient temperature, MeOH (5 mL) was added. The reaction was concentrated in vacuo. Purification by flash chromatography (12 g silica, 0-100% EtOAc/DCM then 0-30% MeOH/DCM) provided (S)-2-(1-aminoethyl)-5-hydroxy-3-phenylquinazolin-4(3H)-on as an orange residue. ES/MS 282.1 (M+H+).
Reaction SMILES: FC(F)(F)[C:3]1C=[C:5]([NH:8][C:9]([C:11]2[C:16]([NH2:17])=[N:15][C:14]([C:18]([F:21])([F:20])[F:19])=[C:13]([Br:22])[N:12]=2)=[O:10])[NH:6][N:7]=1.[NH:25]1C(N)=NC=N1>>[N:7]1[NH:6][C:5]([NH:8][C:9]([C:11]2[C:16]([NH2:17])=[N:15][C:14]([C:18]([F:21])([F:20])[F:19])=[C:13]([Br:22])[N:12]=2)=[O:10])=[N:25][CH:3]=1
Reactant: Nc1ncn[nH]1
Reactant: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)Nc1cc(C(F)(F)F)n[nH]1
Product: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)Nc1ncn[nH]1

Procedure:
The title compound was prepared analogously to 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (5-trifluoromethyl-2H-pyrazol-3-yl)-amide (Example 1) by replacing 3-(trifluoromethyl)-1H-pyrazol-5-amine with 1H-[1,2,4]triazole-5-amine.
Reaction SMILES: N[C@H:2]1[C:21](=[O:22])[N:4]2[C:5]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH2:7][S:8][C@H:3]12.N([O-])=O.[Na+].[Cl-:27].[Na+]>C(O)C.O.Cl>[Cl:27][C@H:2]1[C:21](=[O:22])[N:4]2[C:5]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH2:7][S:8][C@H:3]12
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@H](N)[C@H]2SC1
Reactant: [Cl-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@H](Cl)[C@H]2SC1
Temperature: 0 °C
Yield: 73 %

Procedure:
To an ice-cooled solution of t-butyl 7α-amino-3-acetoxymethyl-3-cephem-4-carboxylate (4.0 g, 0.0122 mol) in 75 ml of ethanol, 16.7 ml of water and 16.7 ml of concentrated hydrochloric acid was added portionwise over 15-20 minutes sodium nitrite (1.18 g, 0.017 mol). The reaction mixture was stirred at 0°-5° C. for 2.5 hours, saturated with sodium chloride, extracted with methylene chloride, washed with water, brine, dried Na2SO4 and concentrated to give 3.1 g (73%) of t-butyl 7α-chloro-3-acetoxymethyl-3-cephem-4carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5](N)=[C:4]([CH3:10])[CH:3]=1.N([O-])=O.[Na+].[Cu](C#N)[C:16]#[N:17].[C-]#N.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>Cl.O.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:16]#[N:17])=[C:4]([CH3:10])[CH:3]=1
Reactant: N#C[Cu]C#N
Reactant: Cc1cc(Br)cc(C)c1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(Br)cc(C)c1C#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
4-Bromo-2,6-dimethylphenylamine (10 g, 500 mmol) was suspended in concentrated HCl (10 mL) and crushed ice (41 g) and cooled to 0° C. NaNO2 (3.52 g, 51 mmol) in water (10 mL) was added, maintaining a temperature of 0° C. and the reaction was stirred for 30 minutes. A solution of copper cyanide (5.60 g, 62.5 mmol) in water (25 mL) and sodium cyanide (7.79 g, 159 mmol) in water (12 mL) were cooled to 0° C. in a separate flask. The concentrated HCl mixture was neutralized with sodium carbonate and the resulting diazonium salt mixture was added to the copper cyanide and sodium cyanide solution along with toluene (100 mL) under vigorous stirring, maintaining a temperature of 0° C. for 1 hour, followed by stirring at room temperature for 4 hours. The reaction mixture was heated to 50° C. and then cooled to room temperature. The reaction was partitioned between water and toluene and the organic layers were combined and washed with water and dried over anhydrous Na2SO4. The product was purified by column chromatography on silica (20% EtOAc/Hexanes) to afford a brown solid (8.10 g). 1H NMR (300 MHz, CDCl3): δ 7.33 (s, 2H), 2.53 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]2[CH2:21][C:22](O)=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[O:23]=[C:22]1[CH2:21][C@@H:16]2[C@H:15]([CH2:20][CH2:19][CH2:18][CH2:17]2)[N:14]1[CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(N[C@H]2CCCC[C@@H]2CC(=O)O)CC1
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: CC(C)(C)OC(=O)N1CCC(N2C(=O)C[C@H]3CCCC[C@@H]32)CC1
Temperature: 25 °C

Procedure:
((1R,2S)-2-{[1-(tert-butoxycarbonyl)piperidin-4-yl]amino}cyclohexyl)acetic acid was dissolved in DMF (3 mL) and diisopropyl ethylamine (50 μL) and HATU (0.1 g, 0.26 mmol) was then added and the mixture stirred at room temperature over night. The solvent was then removed under reduced pressure and the mixture was diluted in dichloromethane. Washed with 1N NaOH and with brine and the solvent was then removed under reduced pressure to give the tile compound. MS (M+1): 323.24
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([N:6]([C:9]1[C:10]([Cl:20])=[N:11][N:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:13]=1)[CH2:7][CH3:8])=[O:5].[F:21][C:22]1([F:29])[CH2:24][C:23]1([CH3:28])[C:25](O)=[O:26].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:20][C:10]1[C:9]([N:6]([CH2:7][CH3:8])[C:4](=[O:5])[CH2:3][CH2:2][NH:1][C:25]([C:23]2([CH3:28])[CH2:24][C:22]2([F:29])[F:21])=[O:26])=[CH:13][N:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:11]=1
Reactant: CCN(C(=O)CCN)c1cn(-c2cccnc2)nc1Cl
Reactant: CC1(C(=O)O)CC1(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCN(C(=O)CCNC(=O)C1(C)CC1(F)F)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-amino-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylpropanamide (0.074 mg, 0.25 mmol), DMAP (0.047 mg, 0.38 mmol), 2,2-difluoro-1-methylcyclopropanecarboxylic acid (0.052 mg, 0.38 mmol) in dry CH2Cl2 (1.69 mL) was cooled to a temperature of about 0° C. under N2. DCC (0.13 g, 0.61 mmol) was added, and the reaction was slowly warmed up to room temperature under N2, then stirred at room temperature overnight. The reaction mixture was filtered using additional CH2Cl2 (0.5 mL) to remove solids and concentrated under reduced pressure. The product was purified by silica gel chromatography eluting with 0%-10% MeOH/CH2Cl2 to afford the title compound F113 as a yellow viscous oil (0.029 g, 26% over 2 steps from compound C2).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:5]([S:18]([C:21]2[CH:26]=[CH:25][C:24](OS(C(F)(F)F)(=O)=O)=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:4][N:3]=1.[CH3:35]B(O)O.C([O-])([O-])=O.[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:5]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:35])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:4][N:3]=1
Reactant: CB(O)O
Reactant: Cc1cc(C)c(Nc2nc(C)ncc2S(=O)(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc2)c(C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)c2cnc(C)nc2Nc2c(C)cc(C)cc2C)cc1
Temperature: 25 °C
Yield: 65.1 %

Procedure:
A mixture of trifluoromethanesulfonic acid 4-[2-methyl-4-(2,4,6-trimethylphenylamino)-pyrimidine-5-sulfonyl]-phenyl ester (158 mg, 0.306 mmol), prepared by the method described in Example 22, methylboronic acid (36 mg, 0.61 mmol), 2 M Na2CO3 (2.0 mL, 4.0 mmol), and DME (4 mL) was degassed with N2 for 10 min, and then PdCl2(PPh3)2 (43 mg, 0.061 mmol) and triphenylphosphine (32 mg, 0.12 mmol) were added. The mixture was refluxed under N2 for 2 h and then cooled to room temperature. The reaction mixture was diluted with water, and extracted (3×) with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (67:33 hexanes/EtOAc) to provide the desired product (76 mg, 65%) as a white solid: mp 202–204° C.; 1H NMR (300 MHz, CDCl3) δ 8.75 (s, 1H), 8.23 (br s, 1H), 7.84 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 6.91 (s, 2H), 2.43 (s, 3H), 2.38 (s, 3H), 2.30 (s, 3H), 2.00 (s, 6H); ESI MS m/z 382 [(M+H)+, calcd for C21H24N3O2S, 382.2].
Reaction SMILES: [SH:1][C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[C:9]([O:13][C:14]([CH2:16][O:17][N:18]=[C:19]([C:51]1[N:52]=[CH:53][S:54][CH:55]=1)[C:20]([NH:22][CH:23]1[C:49](=[O:50])[N:25]2[C:26]([C:33]([O:35][CH:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:34])=[C:27]([CH2:31]Cl)[CH2:28][S:29](=[O:30])[C@H:24]12)=[O:21])=[O:15])([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C.C(OCC)(=O)C>CN(C)C=O.O>[C:9]([O:13][C:14]([CH2:16][O:17][N:18]=[C:19]([C:51]1[N:52]=[CH:53][S:54][CH:55]=1)[C:20]([NH:22][CH:23]1[C:49](=[O:50])[N:25]2[C:26]([C:33]([O:35][CH:36]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)=[O:34])=[C:27]([CH2:31][S:1][C:2]3[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=3)[CH2:28][S:29](=[O:30])[C@H:24]12)=[O:21])=[O:15])([CH3:10])([CH3:11])[CH3:12]
Reactant: Cc1ccc(S)nn1
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS(=O)[C@H]12)c1cscn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c4cscn4)[C@H]3S(=O)C2)nn1
Reaction time: 3 h
Yield: 85.1 %

Procedure:
3-Mercapto-6-methylpyridazine (1 g) was added to a mixture of benzhydryl 7-[2-t-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate-1-oxide (syn isomer) (5.0 g) in N,N-dimethylformamide (25 ml) and triethylamine (0.7 g) under ice-cooling and the mixture was stirred for 3 hours at the same temperature. The reaction mixture was added to a mixture of ethyl acetate and water. The separated organic layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated to give benzhydryl 7-[2-t-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamido]-3-(6-methylpyridazin-3-yl)thiomethyl-3-cephem-4-carboxylate-1-oxide (syn isomer) (4.8 g).
Reaction SMILES: [Br:1][CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].CC(C)=[O:13].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O.S(=O)(=O)(O)O.O.C(OCC)C.[O-2].[O-2].[O-2].[Cr+6]>[Br:1][CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:13])=[O:10]
Reactant: OCCCCCC#CCBr
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOCC
Solvent: CC(C)O
Product: O=C(O)CCCCC#CCBr

Procedure:
To a solution of 2.1 g of 8-bromo-6-octyn-1-ol(prepared as described hereafter) in 20 ml of acetone was added dropwise 7.7 ml of a Jones reagent (prepared by dissolving 6.5 g of chromium trioxide in 5.75 ml of conc. sulphuric acid diluted with water to a volume of 25 ml) at 2° to 5° C. over a period of 40 minutes. To it was added 3 ml of isopropanol. The reaction mixture was diluted with diethyl ether, washed with water, a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure to give crude 8-bromo-6-octynoic acid. The crude product, thus obtained, was dissolved in 20 ml of diethyl ether, and diazomethane-etherate was added with cooling in an ice bath until the solution was coloured pale yellow. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of benzene and ethyl acetate (50:1) as eluent to give 1.583 g of the title compound having the following physical characteristics:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C([Li])CCC.I[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:18]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CCCCCI
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCNc1ccc(C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 23 %

Procedure:
A solution of methyl p-aminobenzoate (0.45 g, 3.0 mmole) in 6 mL tetrahydrofuran (THF) was cooled to −78° C. and treated dropwise with 2.5 M n-butyllithium solution (1.32 mL). The reaction mixture was allowed to warm to 0° C. over a one hour period. Iodopentane (0.78 mL) was introduced at −40° C. and the mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into 50 mL of a saturated aqueous sodium bicarbonate solution and extracted with three portions of 50 mL of ether. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo, giving a brown oil. The product was purified by flash chromatography (SiO2, 10%-20% ethyl acetate/hexanes) to provide 140 mg (23%) of methyl 4-pentylaminobenzoate (43) as a pale yellow oil.
Reaction SMILES: C([S:4][CH:5]([CH3:23])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]([CH3:22])[CH2:17][C:18](=[O:21])[NH:19][N:20]=2)=[CH:11][CH:10]=1)=[O:7])(=O)C.[OH-].[Na+].Cl>CO>[SH:4][CH:5]([CH3:23])[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]([CH3:22])[CH2:17][C:18](=[O:21])[NH:19][N:20]=2)=[CH:13][CH:14]=1)=[O:7]
Reactant: CC(=O)SC(C)C(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(S)C(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1
Yield: 85.8 %

Procedure:
In 20 ml of methanol was dissolved 1.0 g of the compound obtained in Example 31. To this solution was added in a stream of nitrogen 10 ml of 1 N caustic soda solution, and the mixture was reacted for 90 minutes at room temperature. The mixture was made acidic by the addition of 6-N hydrochloric acid to precipitate crystals, which were then collected by filtration and washed with methanol to obtain 750 mg of the end product.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([N:6]1[CH2:17][CH2:16][C:9]2[N:10]=[N:11][C:12]([NH:14][NH2:15])=[CH:13][C:8]=2[CH2:7]1)=[O:5].[CH3:22][C:23]([CH3:25])=O>>[F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([N:6]1[CH2:17][CH2:16][C:9]2[N:10]=[N:11][C:12]([NH:14][N:15]=[C:23]([CH3:25])[CH3:22])=[CH:13][C:8]=2[CH2:7]1)=[O:5]
Reactant: CC(C)=O
Reactant: NNc1cc2c(nn1)CCN(C(=O)c1ccccc1F)C2
Product: CC(C)=NNc1cc2c(nn1)CCN(C(=O)c1ccccc1F)C2

Procedure:
1.0 g of 6-(o-fluorobenzoyl)-3-hydrazino-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine is heated in 10 cc of acetone on a water bath at reflux for 30 minutes. The title compound has a M.P. of 200°-203° (decomp., from absolute ethanol).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[C:18](Cl)[C:17]([CH3:22])=[CH:16]2>CN(C=O)C>[Br:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[C:18]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:17]([CH3:22])=[CH:16]2
Reactant: Oc1ccccc1
Reactant: Cc1cc2cccc(Br)c2nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2cccc(Br)c2nc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.9 %

Procedure:
Phenol (954 mg, 10.14 mmol) was added to a suspension of NaH (60% w/w in mineral oil; 406 mg, 10.14 mmol) in DMF (10 mL) at 0° C. and the resulting solution was stirred at 25° C. for 15 min. 8-Bromo-2-chloro-3-methylquinoline (510 mg, 1.988 mmol) was then added, and the resulting solution was heated at 60° C. for 2.5 d. The mixture was cooled to 25° C. and partitioned between EtOAc (100 mL) and saturated aq. NH4Cl (80 mL). The organic layer was separated, sequentially washed with water (2×50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-10% EtOAc/hexanes) furnished 8-bromo-3-methyl-2-phenoxyquinoline (505.5 mg, 1.609 mmol, 81% yield) as a colorless oil, which was used without further purification in the subsequent step: m/z (ESI, +ve) 314.0 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C[Mg]Br.Cl.Cl[CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1.[Cl-].[NH4+]>C(OCC)C.C1C=CC=CC=1>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH:17]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: ClCc1cccnc1
Agent: C[Mg]Br
Agent: Cl
Agent: [Cl-]
Solvent: CCOCC
Solvent: c1ccccc1
Product: c1cncc(Cc2c[nH]c3ccccc23)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
Under argon, indole (10 g) was dissolved in diethyl ether (100 ml), a 3M methylmagnesium bromide in diethyl ether solution (50 ml) was added at 0° C., and the mixture was stirred at room temperature for 2 hours. 3-Chloromethylpyridine hydrochloride (7 g) and benzene (90 ml) were added at 0° C. and the mixture was refluxed at 110° C. for 8 hours to evaporate the diethyl ether. After the reaction, a saturated ammonium chloride aqueous solution was added, and the mixture was extracted with ethyl acetate, the organic phase was washed with a saturated aqueous sodium hydrogencarbonate solution and brine, then dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography to obtain 3-(3-pyridylmethyl)indole (8.80 g).
Reaction SMILES: C([C:5]1[CH:13]=[C:12](C2C=CC=CC=2)[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]=1[OH:20])(C)(C)C.CC1C=C(C)C=CC=1CCl>[Cl-].[Zn+2].[Cl-].C(O)(=O)C>[CH:12]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([OH:20])=[CH:5][CH:13]=1
Reactant: CC(C)(C)c1cc(-c2ccccc2)cc(C(=O)O)c1O
Agent: Cc1ccc(CCl)c(C)c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: O=C(O)c1ccccc1O
Reaction time: 2 h

Procedure:
A glass-made reactor was charged with 5.4 g (0.02 mole) of 3-tert-butyl-5-phenylsalicylic acid, 30 ml of glacial acetic acid, and as a catalyst, 1.4 g of anhydrous zinc chloride. The resultant mixture was heated under stirring and maintained under reflux. Then, 12.4 g (0.08 mole) of 2,4-dimethylbenzyl chloride was added dropwise over 6 hours to conduct a reaction. After completion of the dropwise addition, the reaction mixture was aged for 2 hours under reflux to complete the reaction. The weight average molecular weight of the thus-obtained resin was 1680.
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=3)[N:16]([CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:15]=2[CH2:37][CH2:38][NH2:39])[CH3:11])=[CH:6][CH:5]=1.[Cl:41][C:42]1[CH:43]=[C:44]([CH2:49][S:50](Cl)(=[O:52])=[O:51])[CH:45]=[CH:46][C:47]=1[Cl:48]>>[CH:24]([N:16]1[C:17]2[C:22](=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:14]([CH2:13][CH2:12][N:10]([CH3:11])[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:40])=[CH:5][CH:6]=2)=[C:15]1[CH2:37][CH2:38][NH:39][S:50]([CH2:49][C:44]1[CH:45]=[CH:46][C:47]([Cl:48])=[C:42]([Cl:41])[CH:43]=1)(=[O:52])=[O:51])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COC(=O)c1ccc(N(C)CCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: O=S(=O)(Cl)Cc1ccc(Cl)c(Cl)c1
Product: CN(CCc1c(CCNS(=O)(=O)Cc2ccc(Cl)c(Cl)c2)n(C(c2ccccc2)c2ccccc2)c2ccc(Cl)cc12)c1ccc(C(=O)O)cc1
Yield: 87 %

Procedure:
The intermediate from example 147 step 7 was treated with 3,4-dichlorophenylmethanesulfonylchloride according to the procedure in Example 87 step 2 to generate the desired product in 87% yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](=[O:16])[CH2:13][CH2:14][Cl:15])[NH:8][C:7](=[O:17])[CH2:6][CH2:5]2.[CH3:18][S:19](Cl)(=[O:21])=[O:20].CN1CCC(=C2C3C(=CC=CC=3)C=CC3C2=CC=CC=3)CC1.[Cl-].[Na+]>CN(C)C=O.N1C=CC=CC=1>[CH3:18][S:19]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](=[O:16])[CH2:13][CH2:14][Cl:15])[NH:8][C:7](=[O:17])[CH2:6][CH2:5]2)(=[O:21])=[O:20]
Reactant: O=C1CCc2cc(O)c(C(=O)CCCl)cc2N1
Reactant: CS(=O)(=O)Cl
Agent: CN1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)Oc1cc2c(cc1C(=O)CCCl)NC(=O)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5.06 Grams of 6-hydroxy-7-(3-chloropropionyl)-3,4-dihydrocarbostyril and 1.8 g of anhydrous pyridine were mixed with 50 ml of dimethylformamide. Then the mixture was cooled with ice and 2.5 g of methanesulfonyl chloride was added to the mixture and stirred at a room temperature for 3 hours. The reactin mixture was poured into 100 ml of a saturated sodium chloride solution and extracted with chloroform. The chloroform layer was washed with water, dried and chloroform was removed by distillation under a reduced pressure to obtain a residue. The residue was crystallized by adding 80 ml of hexane to obtain crude crystals. The crude materials were collected by filtration and were recrystallized from ethanol to obtain 4.5 g of 6-methylsulfonyloxy-7-(3-chloropropionyl)-3,4-dihydrocarbostyril in white crystals.