Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=1)=[N:5][C:6]([S:17][CH3:18])=[N:7]2.O.O.Cl[Sn]Cl.CCO.Cl>O1CCOCC1>[NH2:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=1)=[N:5][C:6]([S:17][CH3:18])=[N:7]2
Reactant: CCOC(=O)c1ccc2nc(SC)nc(-c3cccc([N+](=O)[O-])c3)c2c1N
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc2nc(SC)nc(-c3cccc(N)c3)c2c1N
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a mixture of ethyl 5-amino-2-methylthio-4-(3-nitro-phenyl)-quinazoline-6-carboxylate (example 27e, 1.54 g) and SnCl2.2H2O (4.52 g) in 1,4-dioxane (35 ml) were added EtOH (35 ml) and concentrated aqueous HCl (690 l). The reaction mixture was stirred at 90° C. for 5 h. After cooling to room temperature and concentration under reduced pressure the residue was suspended in EtOAc (35 ml). The mixture was brought to pH 10 by the addition of 2 M NaOH and THF and brine were added. The resulting mixture was stirred for 40 min, after which time the organic layer was seperated, dried (MgSO4) and concentrated under reduced pressure. The title compound was purified by chromatography on silica gel using hept/EtOAc=9/1 to 3/2 (v/v) as eluent.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH:21]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:22][C:23]([O:25][CH3:26])=[O:24]>>[CH3:31][O:30][C:28](=[O:29])[CH2:27][N:21]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:15](=[O:17])[C:14]1[CH:18]=[CH:19][CH:20]=[C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:13]=1
Reactant: COC(=O)CNCC(=O)OC
Reactant: CCCCCCCCCCOc1cccc(C(=O)O)c1
Product: CCCCCCCCCCOc1cccc(C(=O)N(CC(=O)OC)CC(=O)OC)c1

Procedure:
The conversion of 3-(decyloxy)benzoic acid to the acid chloride followed by treatment with dimethyl iminodiacetate as in Example 1 gave N-(2-methoxy-2-oxoethyl)-N-[3-(decyloxy)benzoyl]glycine methyl ester as an oil. The nmr and mass spectra were consistent with the structure.
Reaction SMILES: CO[C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([Cl:10])[CH:5]=1.[CH3:12][C:13]([CH3:15])=[O:14].C[O-].[Na+]>C1COCC1>[Cl:10][C:6]1[CH:5]=[C:4]([C:3](=[O:11])[CH2:12][C:13](=[O:14])[CH3:15])[CH:9]=[CH:8][N:7]=1
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)CC(=O)c1ccnc(Cl)c1
Reaction time: 0.5 h
Yield: 36.2 %

Procedure:
To a solution of methyl-2-chloroisonicotinate (11.93 g, 69.53 mmol) in THF (200 mL) was added acetone (14.19 mL, 153 mmol). The solution was warmed to 35° C. when sodium methoxide (94.13 g, 76.48 mmol) was added sequentially over 20 minutes. The mixture was stirred for 30 minutes, and then brought to reflux for 2.5 hours. The solvent was removed under reduced pressure and then taken up in ethyl acetate. The resulting solution was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and concentrated to yield 1-(2-chloro-4-pyridinyl)-1,3-butanedione (4.97 g, 76%) as a light brown colored solid. This was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[CH2:13][CH2:12][CH2:11][C:10](=[O:15])[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C=O.Cl.[CH3:19]N(C=O)C>C(O)(=O)C>[CH3:1][N:2]1[C:14]2[CH2:13][CH2:12][C:11](=[CH2:19])[C:10](=[O:15])[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: Cn1c2c(c3ccccc31)C(=O)CCC2
Reactant: CN(C)C=O
Agent: C=O
Agent: Cl
Solvent: CC(=O)O
Product: C=C1CCc2c(c3ccccc3n2C)C1=O

Procedure:
Accordingly, 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one was synthesized from 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one using a formaldehyde reagent (paraformaldehyde) and a mineral acid (HCl) in an aprotic solvent (DMF). Note that this reaction was rapid and high yielding, even though it was performed without using glacial acetic acid as a solvent, and without using a secondary amine as a catalyst.
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CN(C)C=O.Cl.[CH3:20][C:21]1([CH3:43])[CH2:26][CH:25]([N:27]2[C:31](=[O:32])[C:30]3=[CH:33][C:34]([C:37](Cl)=[O:38])=[CH:35][CH:36]=[C:29]3[C:28]2=[O:40])[CH2:24][C:23]([CH3:42])([CH3:41])[NH:22]1.C(N(CC)CC)C>C(Cl)Cl.O>[CH3:20][C:21]1([CH3:43])[CH2:26][CH:25]([N:27]2[C:31](=[O:32])[C:30]3=[CH:33][C:34]([C:37]([NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:38])=[CH:35][CH:36]=[C:29]3[C:28]2=[O:40])[CH2:24][C:23]([CH3:42])([CH3:41])[NH:22]1
Reactant: CCCCCCCCCCCCN
Reactant: CC1(C)CC(N2C(=O)c3ccc(C(=O)Cl)cc3C2=O)CC(C)(C)N1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCNC(=O)c1ccc2c(c1)C(=O)N(C1CC(C)(C)NC(C)(C)C1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 125 ml reaction flask equipped with a magnetic stirrer, thermometer, condenser and nitrogen atmosphere were placed 2.4 g (0.013 mol) dodecylamine and 40 ml of 2% dimethylformamide in methylene chloride. This mixture was stirred during the addition of 5.0 g (0.013 mol) of the acid chloride of Example 2 accompanied by an 8° C. exotherm. The reaction mixture was cooled to ambient temperature and 2.8 g (0.028 mol) triethylamine was added, producing an exotherm of about 10° C. The reaction was allowed to stir at room temperature for 30 minutes then transferred to a separatory funnel with 50 ml methylene chloride and 50 ml water. The phases were separated and the organic phase was further extracted with three 50 ml portions of water. Additional solvent, 50 ml, was added and the organic solution washed with two 50 ml portions of 5% sodium hydroxide. The organic solution was dried with anhydrous magnesium sulfate and the solvent stripped using aspirator and high vacuum systems. The product was 6.1 g (98% of theory) of a yellow semi-solid which upon standing became a solid (melting at 42°-45° C.). The infrared spectrum (chloroform) showed two carbonyl absorptions at 1720 cm-1 (imide) and 1660 cm-1 (amide). The NMR spectrum showed the anticipated aromatic ring (7.7-7.9 ppm, doublet, 1H; 8.1-8.3, multiplet, 2H), the amide N--H (6.4-6.8 ppm, multiplet, 1H), the amide methylene (3.2-3.7 ppm, multiplet, 2H) and HALS group and amide residue [4.4-4.9 ppm, multiplet, 1H; 0.7-2.3 ppm, several multiplets].
Reaction SMILES: [Br:1][C:2]1[C:3]([Br:30])=[CH:4][C:5]2[N:11]([C:12](=[O:23])[CH2:13][N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]3)[C:10]3[N:24]=[CH:25][CH:26]=[CH:27][C:9]=3[C:8](=O)[NH:7][C:6]=2[CH:29]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:32]>N1C=CC=CC=1>[Br:1][C:2]1[C:3]([Br:30])=[CH:4][C:5]2[N:11]([C:12](=[O:23])[CH2:13][N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]3)[C:10]3[N:24]=[CH:25][CH:26]=[CH:27][C:9]=3[C:8](=[S:32])[NH:7][C:6]=2[CH:29]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1Nc2cc(Br)c(Br)cc2N(C(=O)CN2CCN(CCO)CC2)c2ncccc21
Solvent: c1ccncc1
Product: O=C(CN1CCN(CCO)CC1)N1c2cc(Br)c(Br)cc2NC(=S)c2cccnc21

Procedure:
In the manner given in Example 1, 8,9-dibromo-6,11-dihydro-11-[[4-(2-hydroxyethyl)piperazino]acetyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one is reacted with phosphorus pentasulfide in pyridine to give 8,9-dibromo-6,11-dihydro-11-[[4-(2-hydroxyethyl)piperazino]acetyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-thione.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][C:16]=1[CH3:17])[NH2:13]>CO.O>[NH2:9][C:10]1[CH:11]=[C:12]([NH:13][C:2]2[N:7]=[C:6]([NH:13][C:12]3[CH:14]=[CH:15][C:16]([CH3:17])=[C:10]([NH2:9])[CH:11]=3)[CH:5]=[CH:4][N:3]=2)[CH:14]=[CH:15][C:16]=1[CH3:17]
Reactant: Clc1ccnc(Cl)n1
Reactant: Cc1ccc(N)cc1N
Solvent: CO
Solvent: O
Product: Cc1ccc(Nc2ccnc(Nc3ccc(C)c(N)c3)n2)cc1N
Temperature: 70 °C

Procedure:
2,4-Dichloropyrimidine (45 mg, 0.30 mmol) was dissolved in a mixture of MeOH (1 ml) and H2O (0.1 ml). 3-amino-4-methylaniline (146 mg, 1.2 mmol) was added and the mixture was refluxed for 20 hours (70° C. oil-bath temperature). The mixture was cooled to 22° C., concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHCl3-Acetone, 2: 1) to give N2,N4-bis(3-amino-4-methylphenyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 8.13 (s, 1H), 6.95 (d, 2H, J=7.5 Hz), 6.82 (d, 2H, J=1.8 Hz), 6.60 (dd, 2H, J=1.8, 7.5 Hz), 6.17 (s, 1H), 2.12 (s, 6H); LCMS purity: 97.3%; MS (m/e): 321.09 (M+, 100).
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[CH:15]=[C:14]([O:16][S:17]([C:20]4[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1.[CH:27]([NH:30][CH2:31][CH2:32][NH2:33])([CH3:29])[CH3:28].[ClH:34]>CN1C(=O)CCC1.CCOC(C)=O>[ClH:34].[CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[CH:15]=[C:14]([O:16][S:17]([C:20]4[CH:25]=[CH:24][C:23]([NH:33][CH2:32][CH2:31][NH:30][CH:27]([CH3:29])[CH3:28])=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1)C1CC1
Reactant: CC(C)NCCN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)NCCNc1ccc(S(=O)(=O)Oc2ccc3nc(NC(=O)C4CC4)sc3c2)cc1

Procedure:
A solution of 4-fluorobenzenesulfonic 2-(cyclopropanecarbonylamino)benzo-thiazol-6-yl ester (example 53, brevetbenzothiazole_V2) (145 mg, 0.37 mmol) and N-isopropylethylenediamine (233 μl, 1.85 mmol) in 4.5 ml of NMP is heated at 150° C. by microwave for 5 minutes. The crude reaction product is diluted with EtOAc, washed 3 times with water and extracted twice with EtOAc. The organic phases are combined, dried over sodium sulfate, filtered and then evaporated to dryness. The 165 mg of crude product are purified by chromatography on silica: 8 g AIT column, eluent: 90/10/1 CH2Cl2/MeOH/—NH4OH. The solid obtained (96 mg) is dissolved in EtOAc and then brought to pH 2 with hydrochloric acid dissolved in EtOAc. The suspension is evaporated to dryness and taken up in 5 ml of water, and then freeze-dried to give 76 mg of 4-(2-isopropylaminoethylamino)benzenesulfonic 2-(cyclo-propanecarbonylamino)benzothiazol-6-yl ester hydrochloride.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl.[CH2:8]([O:15][C:16](Cl)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>CO.O>[N:1]1([C:16]([O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:17])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C1CNCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(OCc1ccccc1)N1CCNCC1
Yield: 48.4 %

Procedure:
A mixture of 17.2 g (0.2 mole) of anhydrous piperazine, 40 ml of water and 60 ml (0.36 mole) of 6N hydrochloric acid in 300 ml of methanol was heated to boiling. Small portions of benzylchloroformate (total 48 g, 0.28 mole) and 4N sodium hydroxide (total 100 ml) were added alternately to maintain a pH of 4.5-5.5. The mixture was heated under reflux for 3 hr, allowed to cool overnight, concentrated in vacuo to remove the methanol, made alkaline with sodium hydroxide and extracted with dichloromethane. The dichloromethane extract was washed with water and then extracted with 400 ml of 1N hydrochloric acid. The acid extract was washed with dichloromethane, made alkaline with sodium hydroxide, and extracted with dichloromethane. The dichloromethane extract was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness in vacuo to give 25 g of crude product. Distillation under vacuum afforded 21.3 g (48%) of the product, bp 140°-143° (0.1 torr). VPC indicated the material consisted of 97% of a single component and the NMR was consistent with the assigned structure.
Reaction SMILES: C1(N[C:8]([NH:10][C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)=[N:13][C:12]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:9])C=CC=CC=1.C1(NC(N)=O)C=CC=CC=1>C(OCC)(=O)C.C(OCC)C>[C:19]1([CH3:22])[CH:20]=[CH:21][C:16]([C:14]2[S:15][C:11]3[NH:10][C:8](=[O:9])[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[C:12]=3[N:13]=2)=[CH:17][CH:18]=1
Reactant: Cc1ccc(-c2nc(-c3ccccc3)c(NC(=O)Nc3ccccc3)s2)cc1
Agent: NC(=O)Nc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1ccc(-c2nc3c([nH]c(=O)c4ccccc43)s2)cc1
Yield: 75 %

Procedure:
To a solution of 1.33 g (5 millimole) of 5-amino-2-(p-tolyl)-4-phenylthiazole in 45 ml of benzene, 0.9 g (7.5 millimole) of the phenylisocyanate in 5 ml of anhydrous benzene is added at room temperature. The reaction mixture is refluxed for 3 hours and 0.45 g (3.75 millimole) of additional phenylisocyanate is added, refluxing is continued for an additional 3 hours, the reaction mixture is cooled and the insoluble part recovered by filtration under vaccum and washed with benzene. On crystallization from ethanol, 1.5 g of the corresponding phenylurea is obtained (M.p. 247°-263° C.; yield 78%). 25 Grams of the resulting 1-phenyl-3-[4-phenyl-2-(p-tolyl)-thiazol-5-yl]urea is heated on a metal bath to a temperature of 300°-305° C.; until aniline distills which, on condensing, dissolves phenylurea which has previously sublimed. After some minutes, the reaction mass is cooled and ethyl acetate-ethyl ether mixture is added thereto. On filtering under vacuum, a substance is recovered which, on crystallization from dimethylformamide, gives 19 g of the desired product (m.p. 314°-316° C.; yield 75%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:11][CH:12]([OH:14])[CH3:13].[NH2:15][C:16]1[CH:23]=[C:22](F)[C:19]([C:20]#[N:21])=[CH:18][N:17]=1>C1COCC1>[NH2:15][C:16]1[CH:23]=[C:22]([O:14][CH:12]([CH3:13])[CH3:11])[C:19]([C:20]#[N:21])=[CH:18][N:17]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: CC(C)O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)Oc1cc(N)ncc1C#N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of KHMDS (87 g, 438 mmol) was added portionwise to a solution of propan-2-ol (26.3 g, 438 mmol) in THF (250 ml) at room temperature. After 15 min a solution of 6-amino-4-fluoronicotinonitrile (intermediate 21, 30 g, 219 mmol) in THF (200 ml) was added and the reaction mixture stirred for 18 h at room temperature. The reaction mixture was partitioned between saturated aqueous NH4Cl and EtOAc, extracted with EtOAc (2×), the combined EtOAc layers were dried over Na2SO4 and evaporated. The residue was triturated with Et2O and the product obtained by filtration as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 6.82 (s, 2H), 6.07 (s, 1H), 4.64 (septet, 1H), 1.31 (d, 6H). (UPLC-MS 7) tR 0.61; ESI-MS 178.1 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>Cl.O>[CH:17]1[CH:18]=[CH:19][C:14]([CH:13]2[O:6][C@H:5]([C@H:3]([OH:4])[CH2:2][OH:1])[C@H:7]([OH:8])[C@H:9]([CH2:11][OH:12])[O:10]2)=[CH:15][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: Cl
Solvent: O
Product: OC[C@@H](O)[C@H]1OC(c2ccccc2)O[C@@H](CO)[C@H]1O

Procedure:
The synthesis of the cyclic sulfate 197, as depicted in Scheme 43, started from the commercially available D-sorbitol (198). Following the reported method by Kuszmann et al.,98 D-sorbitol was first treated with benzaldehyde in hydrochloric acid and water to give 2,4-O-benzylidene-D-glucitol (199). Compound 199 was then reacted with 2,2-dimethoxypropene to afford the 2,4-O-benzylidene-5,6-O-isopropylidene-D-glucitol (200).98 The glucitol derivative 200 was then converted to the cyclic sulfite by treatment with thionyl chloride and pyridine, and the sulfite was then oxidized with sodium periodate and ruthenium(III) chloride as a catalyst to yield the desired cyclic sulfate 197, as a crystalline solid in 75% yield.
Reaction SMILES: C[O:2][C:3](=[O:33])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([CH3:32])(=[O:31])=[O:30])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].[Li+].[OH-]>>[Cl:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([Cl:13])[C:7]=1[C:6]([NH:5][C@H:4]([C:3]([OH:33])=[O:2])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([CH3:32])(=[O:31])=[O:30])=[CH:19][CH:18]=1)=[O:15]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2S(C)(=O)=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: [Li+]
Agent: [OH-]
Product: CS(=O)(=O)c1ccccc1-c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)O)cc1

Procedure:
N-(2,6-dichlorobenzoyl)-4-[2-(methylsulfonyl)phenyl]-L-phenylalanine methyl ester was hydrolyzed with LiOH as described in Example 1-5) to yield N-(2,6-dichlorobenzoyl)-4-[2-(methylsulfonyl)phenyl]-L-phenylalanine (152B). ESMS: m/z 492 (MH+), 514 (M++Na), 491 (M−H)−.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[CH2:6]([OH:22])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(Cl)(Cl)(Cl)Cl>[P:1]([Cl:5])([Cl:3])(=[O:2])[O:22][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCCCCCCO
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCCCCCCCCCCCOP(=O)(Cl)Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a moisture protected solution of 28.4 ml of phosphorous oxychloride in 200 ml of carbon tetrachloride is added dropwise with stirring a solution of 50 g of 1-hexadecanol in 125 ml of carbon tetrachloride. After stirring at ambient temperature for 18 hours, the solvent is removed and the residue evaporated with toluene several times to give 71 g of the desired product as a vacuum dried water white oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:24][CH3:25])=[CH:4][C:5]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)=[N:10][N:9]=[C:8](SC)[CH2:7][C:6]=2[CH:23]=1.[C:26]([NH:31][NH2:32])(=O)[CH2:27][CH2:28][CH3:29]>CN(C=O)C.Cl>[Br:1][C:2]1[C:3]([O:24][CH3:25])=[CH:4][C:5]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)=[N:10][N:9]3[C:26]([CH2:27][CH2:28][CH3:29])=[N:31][N:32]=[C:8]3[CH2:7][C:6]=2[CH:23]=1
Reactant: COc1cc2c(cc1Br)CC(SC)=NN=C2c1ccc([N+](=O)[O-])cc1
Reactant: CCCC(=O)NN
Agent: Cl
Solvent: CN(C)C=O
Product: CCCc1nnc2n1N=C(c1ccc([N+](=O)[O-])cc1)c1cc(OC)c(Br)cc1C2
Temperature: 112.5 °C
Reaction time: 5 h
Yield: 82.8 %

Procedure:
1.17 g (2.78 mmol) of the compound of step B is dissolved in 40 ml of anhydrous DMF and mixed with 0.73 g (8.4 mmol) of butyric acid hydrazide as well as 3 drops of concentrated HCl. The mixture is stirred for 5 hours at 110-115° C. Then, the mixture is poured onto ice (160 g) and stirred for 1 more hour. The precipitated crystals are suctioned off and washed with water. 1.05 g (83%) of 9-bromo-6-(4-nitrophenyl)-8-methoxy-3-propyl-11H-[1,2,4]triazolo[4,3-c][2,3]benzodiazepine with a melting point of 238-240° C. is obtained.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O:24]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20]I)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.C(OC([NH:50][CH2:51][C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1)=O)(C)(C)C.C(OCC)(=O)C>CS(C)=O>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O-:24])=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20][N+:54]4[CH:55]=[CH:56][CH:57]=[C:52]([CH2:51][NH2:50])[CH:53]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: CC(C)(C)OC(=O)NCc1cccnc1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCI)CS[C@H]12)c1nsc(N)n1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C=CC[n+]3cccc(CN)c3)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1.9 %

Procedure:
A mixture of diphenylmethyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(3-iodo-1-propen-1-yl)-3-cephem-4-carboxylate (IX-1) (E, 716 mg, 1 mmole) and 3-(t-butyloxycarbonylaminomethyl)pyridine (516 mg, 2 mmoles) in DMSO (2 ml) was stirred at ambient temperature for 30 minutes. The mixture was poured into ethyl acetate (200 ml), and the precipitate was collected by filtration, washed well with ethyl acetate and dried. A mixture of the quaternized salt (500 mg), sodium bisulfite (50 mg) in HCOOH (5 ml) was stirred at 40°-50° C. for 80 minutes and evaporated to dryness under reduced pressure. The residual solid was dissolved in water (40 ml), and the mixture was neutralized with NaHCO3. Insoluble material was filtered off, and the filtrate was chromatographed on a reverse phase column (packing of PrepPAK-500/C18 cartridge, 100 ml), eluting with water, 5%, 10%, 20% and 30% aqueous CH3OH, successively. The fractions containing the desired compound were combined, evaporated and lyophilized to provide 10 mg (1.8%) of the title compound (I-1I) (E) as a tan powder.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH:13]1[C:18](C(O)=O)=[CH:17][C:16]2[C:22]([O:24][C:25](=O)[C:15]=2[CH:14]=1)=[O:23].[N+](C1C=CC=CC=1)([O-])=O>>[CH:8]1[CH:9]=[C:10]2[CH:11]=[CH:12][C:3]([CH:2]3[C:25](=[O:24])[C:15]4[C:16](=[CH:17][CH:18]=[CH:13][CH:14]=4)[C:22]3=[O:23])=[N:4][C:5]2=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: OCc1ccc2ccccc2n1
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1c2ccccc2C(=O)C1c1ccc2ccccc2n1

Procedure:
As shown by this reaction scheme (5), a hydroxyquinaldine derivative and a trimellitic acid anhydride derivative are added to nitrobenzene, and the mixture is heated and stirred at a refluxing temperature for several hours. Subsequently, the product is collected by filtration and washed with methanol, then dried, to yield the quinophthalone compound of the present invention. Here, a process of removing impurity substances such as inorganic salts can be included. The quinophthalone compound and mixed colorant in the present invention preferably have decreased contents of impurity substances such as inorganic salts, whereby the mechanical properties of the thermoplastic resin can be well maintained, and the anti-migration property and anti-sublimation property can be improved. The content of these impurity substances is desirably not more than 2%.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[CH:26]=[N:27][N:28]([CH3:45])[C:29]=1[N:30]1[CH2:35][C@H:34]([F:36])[CH2:33][C@@H:32]([NH:37]C(=O)OC(C)(C)C)[CH2:31]1)=[O:23])=O)(C)(C)C.N>Cl.CO.CO>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=2[F:20])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[CH:26]=[N:27][N:28]([CH3:45])[C:29]=1[N:30]1[CH2:35][C@H:34]([F:36])[CH2:33][C@@H:32]([NH2:37])[CH2:31]1)=[O:23]
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1C[C@H](F)C[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Agent: N
Solvent: CO
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1C[C@H](N)C[C@@H](F)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 74.2 %

Procedure:
A mixture of tert-butyl (3R,5R)-1-(4-(5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)-thiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-5-fluoropiperidin-3-ylcarbamate (150 mg, 0.23 mmol) in HCl/MeOH (10 mL) was stirred at ambient temperature for 20 hours and concentrated under reduced pressure to afford a residue. The residue was diluted with MeOH (10 mL), neutralized with 28% ammonia solution, and concentrated to give a crude product. The crude product was purified by preparative HPLC to give 159 as pale solid (77 mg, 74%). 1H NMR (500 MHz, CD3OD) δ (ppm): 7.74 (s, 1H), 7.48-7.42 (m, 1H), 7.14-7.11 (m, 2H), 5.36-5.24 (m, 1H), 4.00-3.94 (m, 1H), 3.83-3.72 (m, 4H), 3.42-3.37 (m, 1H), 2.74-2.62 (m, 2H), 2.50-5.42 (m, 1H), 2.02-1.88 (m, 1H); MS (ESI) m/z: 452 [M+H+].