Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[NH:18][NH2:19].CCN=C=NCCCN(C)C>C(#N)C>[C:1]([NH:8][C@H:9]([C:14]([NH:19][NH:18][C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])[CH2:10][CH2:11][S:12][CH3:13])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN=C=NCCCN(C)C
Solvent: CC#N
Product: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)NNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of Boc-L-methionine (9.972 g) [Boc:tert-butoxycarbonyl] and tert-butyl carbazate (5.29 g) in acetonitrile (100 ml) was combined with WSC (9.202 g) and stirred at room temperature for 5 hours. The reaction mixture was concentrated and the resultant residue was combined with ethyl acetate and water, and the organic phase was washed with water, aqueous sodium bicarbonate and brine, dried and concentrated to obtain tert-butyl 2-(Boc-L-methionyl)-1-hydrazine carboxylate as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[S:19][C:5]2[NH:6][C:7](=S)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.[C:20]([NH2:26])(=[O:25])[C:21]([NH:23][NH2:24])=O>CO>[Cl:1][C:2]1[S:19][C:5]2[N:6]3[C:21]([C:20]([NH2:26])=[O:25])=[N:23][N:24]=[C:7]3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)sc2N1
Reactant: NNC(=O)C(N)=O
Solvent: CO
Product: NC(=O)c1nnc2n1-c1sc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
0.8 g of 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione are refluxed in 40 ml of absolute methanol with 1.5 g of oxalic acid amide hydrazide for 1.5 hours. The solution is concentrated to 10 ml and left to crystallize in a refrigerator. The filtered and dried 7-chloro-5-(o-chlorophenyl)-2-(2-oxalylamidohydrazino)-3H-thieno[2,3-e]-1,4-diazepine is refluxed in 100 ml of absolute xylene for 3 hours. The organic phase is evaporated and the residue recrystallized from ethanol to yield 2-chloro-4-(o-chlorophenyl)-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine-9-carboxylic acid amide, melting point 248°-251° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]1=[O:20].O=[C:22]([CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:23]([OH:25])=[O:24].C([BH3-])#N.[Na+]>>[C:17]([CH:9]([N:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C@H:2]([NH:1][CH:22]([C:23]([OH:25])=[O:24])[CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:3]1=[O:20])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([OH:19])=[O:18]
Reactant: N[C@H]1CCCCN(C(Cc2ccccc2)C(=O)O)C1=O
Reactant: O=C(O)C(=O)CCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C(O)C(CCc1ccccc1)N[C@H]1CCCCN(C(Cc2ccccc2)C(=O)O)C1=O

Procedure:
Methyl 2-oxo-3-phenylpropionate and α-t-Boc-L-lysine are condensed in the presence of sodium cyanoborohydride as described in Example 19. Subsequent ring closure to 3-(S)-t-butoxycarbonylamino-1-[1-carbomethoxy-2-phenylethyl]perhydroazepin-2-one is carried out as described in Example 3. Saponification of the methyl ester followed by removal of the t-butoxycarbonyl group affords 3-(S)-amino-1-[1-carboxy-2-phenylethyl]perhydroazepin-2-one. The caprolactam and 2-oxo-4-phenylbutyric acid are condensed in the presence of sodium cyanoborohydride to yield 1-[1-carboxy-2-phenylethyl]-3-(S)-[(1-carboxy-3-phenylpropyl)amino]perhydroazepin-2-one.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([NH:8][CH2:9][CH3:10])=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=1.[C:16]([C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1)#[N:17].O>O1CCCC1>[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([N:8]([CH2:9][CH3:10])[S:24]([C:21]2[CH:20]=[CH:19][C:18]([C:16]#[N:17])=[CH:23][CH:22]=2)(=[O:26])=[O:25])=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCNc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCN(c1ccc(Cl)cc1[N+](=O)[O-])S(=O)(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Yield: 64.6 %

Procedure:
To a suspension of sodium hydride (60%, 0.10 g (2.50 mmol)) in tetrahydrofuran (THF)(3.0 ml), 4-chloro-N-ethyl-2-nitroaniline (0.40 g (1.99 mmol)) was added with stirring at room temperature. To the mixture, after stirring for 30 minutes at room temperature, 4-cyanobenzenesulfonyl chloride (0.50 g (2.48 mmol)) was added and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water and the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:2) as eluent, to give 0.47 g (64%) of the title compound as pale yellow crystals.
Reaction SMILES: [CH2:1]([S:7][S:8][CH2:9][C@H:10]([NH2:14])[C:11]([OH:13])=[O:12])[C@H:2]([NH2:6])[C:3]([OH:5])=[O:4].[CH3:15][C:16]([S:21][CH3:22])([CH3:20])[C:17](Cl)=[O:18]>[OH-].[Na+]>[CH3:15][C:16]([S:21][CH3:22])([CH3:20])[C:17]([NH:6][C@H:2]([C:3]([OH:5])=[O:4])[CH2:1][S:7][S:8][CH2:9][C@H:10]([NH:14][C:17](=[O:18])[C:16]([S:21][CH3:22])([CH3:20])[CH3:15])[C:11]([OH:13])=[O:12])=[O:18]
Reactant: N[C@@H](CSSC[C@H](N)C(=O)O)C(=O)O
Reactant: CSC(C)(C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Product: CSC(C)(C)C(=O)N[C@@H](CSSC[C@H](NC(=O)C(C)(C)SC)C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83.6 %

Procedure:
To a stirred solution of 3.1 g (13 mM) of L-cystine in 105 ml of 0.5 N sodium hydroxide, 4.0 g (26 mM) of 2-methyl-2-(methylthio)propanoyl chloride is added dropwise at 5°-10° C. After the addition the reaction mixture is stirred for 45 minutes at the same temperature and for additional 20 minutes at the room temperature. The reaction mixture is washed with ether, acidified with 6N hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with water and dried. Ehtyl acetate is distillated off and the residue is purified by silica gel column chromatography to give 5.1 g (83%) of the titled compound.
Reaction SMILES: [C:1](Cl)(=O)[O:2]C(Cl)(Cl)Cl.[NH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:11]=1[C:12]([OH:14])=[O:13].C(OCC)C>O1CCOCC1>[CH3:19][C:15]1[C:11]2[C:12](=[O:14])[O:13][C:1](=[O:2])[NH:9][C:10]=2[CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1cccc2[nH]c(=O)oc(=O)c12
Yield: 56 %

Procedure:
Trichloromethyl carbonochloridate (2.04 mL, 16.9 mmol) was added to 2-amino-6-methylbenzoic acid (2.13 g, 14.1 mmol) in anhydrous dioxane (32 mL) under nitrogen, then refluxed for 30 minutes. Diethyl ether (100 mL) was added, and the precipitated solid was collected by filtration to give 5-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (1.4 g, 56%) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[C:10]([CH3:16])=[C:11]([C:13](Cl)=[O:14])[N:12]=2)=[CH:4][CH:3]=1.[NH2:25][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[C:10]([CH3:16])=[C:11]([C:13]([NH:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:14])[N:12]=2)=[CH:4][CH:3]=1
Reactant: NN1CCCCC1
Reactant: Cc1c(C(=O)Cl)nc(-c2ccc(Cl)cc2)n1-c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2)n1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.6 %

Procedure:
Part C: 2-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carbonyl chloride (1.5 gram, 3.75 mmol), 1-aminopiperidine (0.725 gram, 7.25 mmol) and triethylamine (0.549 gram, 5.44 mmol) are dissolved in dichloromethane and stirred for one hour at room temperature. The mixture is washed with a saturated aqueous NaHCO3 solution, dried over Na2SO4 and concentrated in vacuo and further purified by column chromatography (heptane/ethyl acetate=1/1 (v/v), silicagel) to give 2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-5-methyl-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide (0.220 gram, 13% yield) as a white foam. MS: 463.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:21](Cl)(=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([C:21]2[O:13][C:12](=[O:14])[C:3]3[CH:4]=[C:5]4[C:10]([CH2:9][CH2:8][CH2:7][CH2:6]4)=[CH:11][C:2]=3[N:1]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cc2c(cc1C(=O)O)CCCC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=c1oc(-c2ccccc2)nc2cc3c(cc12)CCCC3
Temperature: 25 °C
Yield: 44.5 %

Procedure:
2-Phenyl-6,7,8,9-tetrahydro-naphtho[2,3-d][1,3]oxazin-4-one was prepared by a modification of the route described in Okabe, M. and Sun, R. C.; Tetrahedron 1995, 51(7), 1861-1866. A 100 mL flask was charged with 3-amino-5,6,7,8-tetrahydro-napthalene-2-carboxylic acid, prepared in 36% yield as described in WO 2007/081572 (360 mg, 1.88 mmol) and sodium carbonate (399 mg, 3.77 mmol) and was then evacuated and backfilled with dry nitrogen gas twice before the addition of anhydrous tetrahydrofuran (50 mL). Cooled in an ice bath and added benzoyl chloride (662 mg, 4.71 mmol) and allowed to warm to ambient temperature overnight with stirring. Evaporated in vacuo and partitioned between ethyl acetate and water (20 mL each). Organic fraction was separated, dried with a hydrophobic frit, evaporated onto silica gel, and chromatographed using ISCO Companion with a Redisep silica gel 12 g cartridge and a gradient of heptane and ethyl acetate (0% to 50%). Impure fractions were combined and crystallized from refluxing heptane solution (˜100 mL). Pure material from the column was combined with material obtained by crystallization to give 2-phenyl-6,7,8,9-tetrahydro-naphtho[2,3-d][1,3]oxazin-4-one as a white solid 232.3 mg (44.5% Yield) LCMS (5 min acidic) 3.19 min 100% pure by ELSD, 36-100% pure by UV, ES+/AP+ 278. HNMR (CDCl3) >95% Pure 8.31-8.29 (m, 2H), 7.96 (s, 1H), 7.57-7.47 (m, 3H), 7.41 (s, 1H), 2.95-2.92 (m, 4H), 1.89-1.86 (m, 4H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[CH2:18]([O:20][CH2:21][CH2:22][CH2:23][NH2:24])[CH3:19].C([O-])([O-])=O.[K+].[K+]>O>[CH2:18]([O:20][CH2:21][CH2:22][CH2:23][NH:24][C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2[C:3]=1[N:11]=[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:9]=2)[CH3:19]
Reactant: CCOCCCN
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOCCCNc1nc(C)[nH]c2cc(-c3ccccc3)nc1-2
Yield: 44 %

Procedure:
This compound was prepared according to the method described in Example 26 by employing 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (0.10 g, 0.41 mmol) with 3-ethoxypropylamine (Aldrich Chemical Company) (0.225 g, 2.18 mmol) and K2CO3 (0.34 g, 2.50 mmol) in H2O (2.5 mL) to give a biphasic reaction mixture, which was partitioned between CH2Cl2 and H2O. The organic layers were separated, dried over MgSO4 and concentrated. The resulting yellow oil was purified by flash chromatography on silica gel (1:40 MeOH/CH2Cl2 followed by 1:20 MeOH/CH2Cl2 as eluant) to give 0.056 g (44%) of the title compound as a light yellow oil that solidified upon standing. Mp: 208-209.5° C. 1H NMR (CDCl3; 500 MHz): δ 1.16 (t, 3, J=7.0), 1.99 (quin, 2, J=5.8, 6.4), 2.58 (s, 3), 3.52 (q, 2, J=7.1), 3.63 (t, 2, J=5.6), 3.74 (t, 2, J=6.6), 5.95 (br s, 1), 6.67 (s, 1), 7.33 (t, 1, J=7.4), 7.40 (t, 2, J=7.6), 7.66 (d, 2, J=7.6); MS m/z: 311 (M+1).
Reaction SMILES: [C:1]([NH:4][CH2:5][C@H:6]1[C@H:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[O:11][CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1)(=[O:3])[CH3:2].C(OCC)(=O)C.Cl>C(O)C>[Cl:20][C:15]1[CH:14]=[C:13]([C@@H:12]2[O:11][CH2:10][CH2:9][NH:8][CH2:7][C@H:6]2[CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: CC(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)NC[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.4 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-[(acetylamino)methyl]-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (160 mg) in ethanol (0.5 mL) was added 4.0 M hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 1.5 hr. The solvent was evaporated under reduced pressure. To the residue was added 1 N aqueous sodium hydroxide solution, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in ethanol, and a solution of fumaric acid (39.3 mg) in ethanol was added. The solvent was evaporated under reduced pressure. The obtained crystals were recrystallized from ethanol-ethyl acetate to give the title compound (73.5 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:30][Cl:31])=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)=[CH:13][C:12]([O:26][CH3:27])=[C:11]([O:28][CH3:29])[CH:10]=2)=[O:5])[CH3:2].ClC1C=CC=C(C(OO)=[O:40])C=1>CO>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:30][Cl:31])=[N+:8]([O-:40])[C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)=[CH:13][C:12]([O:26][CH3:27])=[C:11]([O:28][CH3:29])[CH:10]=2)=[O:5])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Solvent: CO
Product: CCOC(=O)c1c(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc2[n+]([O-])c1CCl
Reaction time: 2 h
Yield: 64.4 %

Procedure:
A mixture of 2-chloromethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylic acid ethyl ester (3.0 g), m-chloroperbenzoic acid (85%, 2.3 g) and methanol (40 ml) was stirred under refluxing conditions for 2 hours. The reaction mixture was distilled under reduced pressure to remove the solvent. The residue was poured over chloroform. The chloroform layer was washed with water and dried (MgSO4), after which the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with chloroform-ethyl acetate (6:4, v/v) to yield 2-chloromethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylic acid ethyl ester 1-oxide (2.0 g, 65%), which was then recrystallized from acetone-isopropyl ether to yield a colorless prismatic crystal having a melting point of 193° to 194° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=2)=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:3]=1.[Cl:31][CH2:32][C:33](Cl)=[O:34]>CC#N>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][CH2:10][CH2:11][N:12]([CH2:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=2)[C:33](=[O:34])[CH2:32][Cl:31])=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:3]=1
Reactant: CCCCCNc1nc(N)nc(C)c1CCCNCc1cccc(CC(=O)OC)c1
Reactant: O=C(Cl)CCl
Solvent: CC#N
Product: CCCCCNc1nc(N)nc(C)c1CCCN(Cc1cccc(CC(=O)OC)c1)C(=O)CCl
Reaction time: 16 h

Procedure:
The product from Example 1 (0.1 g) was dissolved in MeCN (10 mL) and chloroacetyl chloride (0.027 g) was added. The reaction mixture was stirred for 16 h and the solvents evaporated to give the subtitle compound which was used without further purification.
Reaction SMILES: [CH2:1]([N:5]([CH2:24][CH2:25][CH2:26][CH3:27])[C:6]1[CH:22]=[CH:21][C:9]([C:10]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])=[O:11])=[C:8]([OH:23])[CH:7]=1)[CH2:2][CH2:3][CH3:4].C[C:29]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=1[NH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>S(=O)(=O)(O)O>[CH2:24]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:22]=[CH:21][C:9]([C:10]2([C:34]3[CH:29]=[C:30]([NH:37][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:31]=[CH:32][C:33]=3[O:35][CH3:36])[C:12]3[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:14](=[O:15])[O:11]2)=[C:8]([OH:23])[CH:7]=1)[CH2:25][CH2:26][CH3:27]
Reactant: COc1ccc(Nc2ccccc2)c(C)c1
Reactant: CCCCN(CCCC)c1ccc(C(=O)c2ccccc2C(=O)O)c(O)c1
Agent: O=S(=O)(O)O
Product: CCCCN(CCCC)c1ccc(C2(c3cc(Nc4ccccc4)ccc3OC)OC(=O)c3ccccc32)c(O)c1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
There is described in Japanese Patent Laid-open No. 60-202155 that a known conventional method provides a low melting type 3-dibutylamino-6-methyl-7-anilinofluoran. The conventional method is as follows. 2-(4-Dibutylamino-2-hydroxybenzoyl)benzoic acid and 4-methoxy-2-methyldiphenylamine are dissolved in concentrated sulfuric acid, and the reaction is carried out at 0°-5° C. for 20 hours. After the reaction, the reaction mixture is poured into ice water, whereupon precipitates are formed. The precipitates are collected by filtration and washed with water to provide a cake of 3-(4-dibutylamino-2-hydroxyphenyl)-3-(5-anilino-2-methoxyphenyl)phthalide. The cake is added to a mixture of toluene and water, and then the mixture is neutralized with a 28% by weight aqueous solution of sodium hydroxide. A further amount of sodium hydroxide is added and then the mixture is stirred at a refluxing temperature for three hours. After the reaction, the mixture is left standing, and a toluene layer is separated and concentrated at 70° C. until a syrup is obtained. Methanol is added to the syrup so that 3-dibutylamino-6-methyl-7-anilinofluoran crystalizes out. According to the reference, the obtained compound has a melting point of 148°-152° C.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[C:25]([Cl:27])[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:8]=1)=[O:5].O1CCOCC1.Br[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:1][C:2]1[CH:26]=[C:25]([Cl:27])[C:24]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:8]=1)=[O:5]
Reactant: CCOC(=O)c1cc(NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Reactant: Brc1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(NC(=O)c2cc(-c3ccccn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Yield: 21 %

Procedure:
To the solution of ethyl 5-(2,4-dichloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylate in dioxane (Preparation 4, 675 mg, 1.27 mmol) was added water (2.2 mL), 2-bromopyridine (302 mg, 1.91 mmol) and K2CO3 (352 mg, 2.546 mmol). The reaction was degassed for 10 minutes before the addition of tetrakis(triphenylphosphine)palladium(0) (147 mg, 0.127 mmol) and heating at reflux for 2 hours. The reaction was cooled and concentrated in vacuo. The residue was purified using silica gel chromatography eluting with 20-50% EtOAc in heptanes to afford the title compound (128 mg, 21%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][S:15][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19].[Al+3].[Cl-].[Cl-].[Cl-]>ClC(Cl)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([C:18](=[O:19])[C:17]([CH3:22])([CH3:21])[CH3:16])[S:15][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOC(=O)N1CCc2ccsc2CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)N1CCc2cc(C(=O)C(C)(C)C)sc2CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27.3 %

Procedure:
A solution of the product from Example 1, step (d) (160 mg, 0.71 mmol) in dichloroethane (5 ml) at 0° C. was treated with trimethyl acetyl chloride (0.17 ml, 1.42 mmol) and AlCl3 (190 mg, 1.42 mmol). The reaction mixture was allowed to stir at 0° C. for 30 minutes and then allowed to warm to room temperature. The reaction mixture was quenched by the addition of saturated solution of NaHCO3 (30 ml) and extracted with dichloromethane (3×30 ml). The combined organic extracts were washed with brine (50 ml), dried (MgSO4), and solvent evaporated in vacuo to give a tan oil. The crude oil was purified by silica gel chromatography (0% to 50% EtOAc in Hex) to give the subtitle compound as a clear oil (60 mg, 27%). MS: ESI (positive): 310 (M+H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[C:14]([F:20])=[C:15](F)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[C:27]1([CH:33]2[CH2:38][NH:37][CH2:36][CH2:35][NH:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[C:14]([F:20])=[C:15]([N:37]5[CH2:36][CH2:35][NH:34][CH:33]([C:27]6[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=6)[CH2:38]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Reactant: c1ccc(C2CNCCN2)cc1
Product: CCOC(=O)c1cn(C2CC2)c2nc3c(F)c(N4CCNC(c5ccccc5)C4)c(F)cc3cc2c1=O
Yield: 71.8 %

Procedure:
(RS)-1-Cyclopropyl-3-ethoxycarbonyl-7,9-difluoro-4-oxo-8-(3-phenyl-1-piperazinyl)-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 19, but starting with 1-cyclopropyl-3-ethoxycarbonyl-7,8,9-trifluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.8 g) and (RS)-2-phenylpiperazine (3.2 g). After recrystallization in a mixture of dimethylformamide (5 cc) and ethanol (40 cc), (RS)-1-cyclopropyl-3-ethoxycarbonyl-7,9-difluoro-4-oxo-8-(3-phenyl-1-piperazinyl)-1,4-dihydrobenzo[b][1,8]naphthyridine (1.8 g) is obtained in the form of a yellow solid, m.p. 242° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[N:13][CH:14]=2)[O:3]1.CI.[C:26](=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:26][N:15]([C:12]1[N:11]=[CH:10][C:9]([B:4]2[O:3][C:2]([CH3:23])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:14][N:13]=1)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)Nc1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Product: CN(C(=O)OC(C)(C)C)c1ncc(B2OC(C)(C)C(C)(C)O2)cn1

Procedure:
Tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-ylcarbamate (250 mg) was treated with 3 equivalents methyl iodide and cesium carbonate at room temperature for one hour. The crude reaction mixture was extracted with ethyl acetate and water. The initial organic layer is discarded. The aqueous layer was acidified to pH 5 and the product was extracted out of the aqueous with ethyl acetate. This organic layer was dried with magnesium sulfate, filtered and concentrated to give 150 mg crude tert-butyl methyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-ylcarbamate.