Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH:4]=1.[CH3:19][O:20][C:21](=[O:28])[C@H:22]([CH2:24][CH2:25][S:26][CH3:27])[NH2:23].Cl.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[CH3:19][O:20][C:21](=[O:28])[C@H:22]([CH2:24][CH2:25][S:26][CH3:27])[NH:23][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([CH2:2][OH:1])=[CH:4][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: Cc1ccccc1-c1cc(CO)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CO)cc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Hydroxymethyl-2-(2-methylphenyl)benzoic acid (69 g, 285 mmol), prepared as in example 1075E, L-methionine methyl ester.HCl (68.3 g, 342 mmol), 1-hydroxybenzotriazole (46.2 g, 342 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (65.6 g, 342 mmol) were dissolved at ambient temperature in DMF (700 mL). To this solution was added triethylamine (47.7 mL, 342 mmol) and the resulting thick slurry was stirred overnight at ambient temperature. The reaction was diluted with EtOAc (700 mL) and washed with water (2×1L), saturated NaHCO3 (2×500 mL), 1N H3PO4 (2×500 mL), and brine. Organic layer dried with Na2SO4, filtered, and concentrated in vacuo to produce a pale yellow solid (110 g, 100% crude yield). 1H(300 MHz, CDCl3) δ 7.93 (1H, m), 7.44 (1H, dd, J=8, 2 Hz), 7.40-7.20 (4H, m), 7.19 (1H, bs), 5.92 (1H, m), 4.78 (2H, s), 4.63 (1H, m), 3.66 (3H, s), 2.20-2.00 (8H, m), 1.87 (1H, m), 1.75 (1H, m), 1.60 (1H, m). m/e (ESI) 386 (MH−).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]1([N:12](CC)[C:13]([NH:15][CH2:16][CH3:17])=O)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[CH:20]([NH:23][CH:24]([CH3:26])[CH3:25])([CH3:22])C.[OH-].[Na+].[C:29]1(C)[CH:34]=CC=C[CH:30]=1>O>[CH:6]1([N:12]=[C:13]([N:15]([CH2:16][CH3:17])[CH:29]([CH3:34])[CH3:30])[N:23]([CH2:20][CH3:22])[CH:24]([CH3:26])[CH3:25])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CC(C)NC(C)C
Reactant: CCNC(=O)N(CC)C1CCCCC1
Reactant: Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCN(C(=NC1CCCCC1)N(CC)C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phosphorus oxychloride (78.2 g, 0.51 mol) is added dropwise over 1 hour period to a toluene (250 ml) solution of cyclohexyl-diethylurea (99 g, 0.5 mol). The reaction is stirred overnight at room temperature. Diisopropylamine (101 g, 1.0 mol). is added dropwise for over a 1 hour period, then stirred 2 hours at room temperature. The reaction mixture is poured into water (300 ml). The water layer is extracted with toluene (3×100 ml) and the toluene layers are discarded. Sodium hydroxide (120 g, 3 mol) is slowly added to the aqueous layer in an ice-water bath. Two layers formed and the aqueous layer is extracted with diethylether (2×100 ml). The organic layer and extracts are combined and dried over Na2CO3, filtered and concentrated. The residue is further distilled under vacuum (ca, 0.3-0.5 torr) collecting product, cyclohexyl-diethyl-diisopropylguanidine, at 137°-140° C. (95 g, 68%) of 99% purity as judged by gas chromatography. 1H NMR (CDCl3) δ 3.57 (m, 1H), 3.36 (m, 1H), 3.21 (q, 2H), 2.94 (q, 2H, 3.12 (m, 1H0, 2.93 (q, 2H), 1.13-1.77 (m, 10H), 1.20 (d, 6H), 1.12(d, 6H), 1.00 (t, 3H), 0.99 (t, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19].[CH:22]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]O)[CH:33]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[CH:22]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][O:16][C:13]3[CH:14]=[N:15][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:11]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=3)[CH:33]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23]1
Reactant: CCOC(=O)CC(c1cccc(CO)c1)C1CC1
Reactant: COc1ccc(F)c(-c2ncc(O)cc2CC(C)(C)C)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1cccc(COc2cnc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Reaction time: 14 h
Yield: 47 %

Procedure:
Under a nitrogen atmosphere, to a solution of 6-(2-fluoro-5-methoxyphenyl)-5-neopentylpyridin-3-ol (300 mg), ethyl 3-cyclopropyl-3-(3-(hydroxymethyl)phenyl)propanoate (257 mg) and triphenylphosphine (554 mg) in THF (5.0 mL) was added a 40% solution of diethyl azodicarboxylate in toluene (943 μL) at room temperature, and the mixture was stirred for 14 hr. The solvent of the reaction mixture was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (253 mg) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:14]([F:15])=[CH:13][C:12]([C:16](O)=[O:17])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([CH:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:8][C:9]=1[NH:10]2.C(Cl)CCl.C1C=CC2N(O)N=[N:40]C=2C=1.[NH4+].[OH-]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[C:14]([F:15])=[CH:13][C:12]([C:16](=[O:17])[NH2:40])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:8][C:9]=1[NH:10]2
Reactant: CCOC(=O)C(C(=O)OCC)C1CCc2c([nH]c3c(C(=O)O)cc(F)c(Br)c23)C1
Reactant: On1nnc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCOC(=O)C(C(=O)OCC)C1CCc2c([nH]c3c(C(N)=O)cc(F)c(Br)c23)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 5-bromo-2-(1,3-diethoxy-1,3-dioxopropan-2-yl)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid (0.981 g, 2.09 mmol), EDC (0.600 g, 3.13 mmol) and HOBT (0.383 g, 2.50 mmol) in THF (5 mL) was stirred at room temperature for 60 min. The mixture was treated with NH4OH (1.74 mL, 12.5 mmol) and stirred at room temperature overnight. The mixture was diluted with EtOAc, washed sequentially with saturated aqueous Na2CO3 and brine. The combined aqueous layers were extracted with EtOAc, and the combined organic phases were dried and concentrated. The residue was purified by column chromatography on silica gel (40 g), eluting with EtOAc-hexanes (gradient from 0-100%), to provide diethyl 2-(5-bromo-8-carbamoyl-6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)malonate as a slightly yellow solid (440 mg, 45% yield). Mass spectrum m/z 469, 471 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][C:8](Cl)=[O:9])(=[O:4])=[O:3].[C:11]([O:15][C:16](=[O:47])[NH:17][C:18]([C:20]1[S:21][C:22]([S:45][CH3:46])=[C:23]([S:25]([C:28]2[CH:29]=[C:30]([C:34]3[C:39]([NH2:40])=[CH:38][C:37]([N+:41]([O-])=O)=[CH:36][C:35]=3[CH3:44])[CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH:24]=1)=[NH:19])([CH3:14])([CH3:13])[CH3:12].CCN(CC)CC>C(Cl)Cl>[C:11]([O:15][C:16](=[O:47])[NH:17][C:18]([C:20]1[S:21][C:22]([S:45][CH3:46])=[C:23]([S:25]([C:28]2[CH:29]=[C:30]([C:34]3[C:39]([NH:40][C:8](=[O:9])[CH2:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:38][C:37]([NH2:41])=[CH:36][C:35]=3[CH3:44])[CH:31]=[CH:32][CH:33]=2)(=[O:26])=[O:27])[CH:24]=1)=[NH:19])([CH3:14])([CH3:13])[CH3:12]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc([N+](=O)[O-])cc2N)c1
Reactant: CS(=O)(=O)CCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(N)cc2NC(=O)CCCS(C)(=O)=O)c1
Reaction time: 1 h

Procedure:
The procedure in Example 261: step b was followed using 4-methanesulfonyl-butyryl chloride (Example 209: step a (53 mg, 0.29)), {[4-(6′-amino-2′-methyl-4′-nitro-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester ((Example 295: step h) 130 mg, 0.23 mmol), and Et3N (192 μL, 1.38 mmol) in DCM (5 mL). After stirring for 1 h, starting material remained and an additional 20 mg of acid chloride was added. The solution was partitioned between EtOAc (70 mL) and aq NH4Cl (30 mL) and the layers were separated. The organic layer was washed with NaHCO3 (20 mL) and brine (30 mL) and was dried over sodium sulfate. The solution was concentrated and the residue was purified by SiO2 flash column chromatography to yield 126 mg of the amide product. The residue dissolved in EtOH (5 mL). Saturated aqueous NH4Cl (1.5 mL) was added followed by iron powder (110 mg, 2 mmol). The mixture was vigorously stirred at 80° C. for 30 min. The solution was filtered through a 0.22 μm filter and was then partitioned between EtOAc (70 mL) and water (20 mL). The layers were separated, the organic solution was dried over sodium sulfate, and the solution was concentrated to give the crude title compound which was used without further purification. 1HMR (CDCl3): δ 7.99 (s, 1H), 7.96 (m, 2H), 7.77 (s, 1H), 7.57 (t, 1H, J=7.9 Hz), 7.43 (dt, 1H, J=1.3, 7.7 Hz), 7.10 (br s, 1H), 7.04 (br s, 1H), 6.43 (br s, 1H), 3.85 (br s, 2H), 2.92 (m, 2H), 2.88 (s, 3H), 2.56 (s, 3H), 2.20 (t, 2H, J=6.7 Hz), 1.98 (m, 2H), 1.90 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: [OH:1][PH2:2]=[O:3].[Cl-].[C:5]1([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH2:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:19]1([CH2:25][CH:26]=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[CH:11]([NH:12][CH:26]([PH:2](=[O:1])[OH:3])[CH2:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=CCc1ccccc1
Reactant: O=[PH2]O
Reactant: NC(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: CCO
Product: O=[PH](O)C(Cc1ccccc1)NC(c1ccccc1)c1ccccc1
Temperature: 87.5 °C
Reaction time: 16 h

Procedure:
51.5 ml of a 50% aqueous solution of H3PO2 are added to a suspension of 109.5 g of diphenylmethanamine chloride in 750 ml of ethanol 90%, and then the reaction mixture is heated to 85-90° C. At that temperature, 58.4 ml of phenylacetaldehyde in 175 ml of ethanol are added over a period of 3 hours, and heating is continued for 3 more hours, followed by stirring for 16 hours at ambient temperature. The precipitate that is formed is filtered off, washed with cold ethanol and with diethyl ether and then dried, thereby allowing the expected product to be isolated.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH2:12][CH2:13][CH2:14][OH:15])[C:5]([CH3:16])=[C:4]([CH3:17])[N:3]=1.[N-:18]=[N+:19]=[N-:20].[Na+].O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].C(#N)C>CN(C=O)C.O>[CH3:17][C:4]1[N:3]2[N:18]=[N:19][N:20]=[C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH2:12][CH2:13][CH2:14][OH:15])[C:5]=1[CH3:16]
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCO)c1C
Reactant: [N-]=[N+]=[N-]
Agent: [Ce+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1c(NCCCO)c([N+](=O)[O-])c2nnnn2c1C
Temperature: 25 °C
Yield: 75.4 %

Procedure:
A mixture of 3-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]propan-1-ol (12.4 g, 47.8 mmol), sodium azide (6.20 g, 95.5 mmol), and cerium (III) chloride heptahydrate (8.90 g, 23.9 mmol) in 9:1 acetonitrile:water (160 mL) was heated at reflux for 16 hours, then was allowed to cool to room temperature. DMF was added and the mixture was filtered. The filter cake was washed with DMF. The filtrate was concentrated under reduced pressure to give an orange solid that was triturated with ethyl acetate and isolated by filtration to yield 9.60 g of 3-[(5,6-dimethyl-8-nitrotetraazolo[1,5-α]pyridin-7-yl)amino]propan-1-ol as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[OH:11][C:12]1[CH:13]=[CH:14][C:15]2[C:19]([C:20]([O-:22])=[O:21])=[C:18]([CH3:23])[S:17][C:16]=2[CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:23][C:18]1[S:17][C:16]2[CH:24]=[C:12]([O:11][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[CH:9][S:10][C:3]=34)[CH:13]=[CH:14][C:15]=2[C:19]=1[C:20]([OH:22])=[O:21]
Reactant: Cc1sc2cc(O)ccc2c1C(=O)[O-]
Reactant: Clc1ccnc2ccsc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1sc2cc(Oc3ccnc4ccsc34)ccc2c1C(=O)O
Yield: 27.2 %

Procedure:
This material was prepared by reacting 7-chlorothieno[3,2-b]pyridine (170 mg, 1.0 mmole) with methyl 6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylate 11a (267 mg, 1.2 mmole) and Cs2CO3 (488 mg, 1.5 mmole) in a manner similar to that previously described for example 1. Silica gel chromatography (10% MeOH/CHCl2) provided the title compound as a brown viscous oil (93 mg, 27%) of. 1H NMR (DMSO-d6, 300 MHz) δ8.47 (1H, d, J=5.27 Hz), 8.41 (1H, d, J=8.85 Hz), 8.11 (1H, d, J=5.46 Hz), 7.93 (1H, d, J=2.07 Hz), 7.55 (1H, d, J=7.55 Hz), 7.32 (1H, dd, J=2.26, 8.85 Hz), 6.64 (1H, d, J=5.27 Hz), 2.77 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[CH3:13][NH:14][O:15][CH3:16].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>N1C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([N:14]([O:15][CH3:16])[CH3:13])=[O:8]
Reactant: O=C(O)c1cc(Br)ccc1F
Reactant: CNOC
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: c1ccncc1
Solvent: O
Product: CON(C)C(=O)c1cc(Br)ccc1F
Yield: 90.5 %

Procedure:
A solution of compound 13 (98.0 g, 447 mmol), N,O-dimethylhydroxylamine hydrochloride (52.4 g, 537 mmol), and BOP-Cl (171 g, 671 mmol) in pyridine (490 mL) was stirred at room temperature for 3 h. After this time, the reaction mixture was diluted with water (1 L) and extracted with ethyl acetate (2×1 L). The combined extracts were washed with 1 N hydrochloric acid (3×500 mL), saturated aqueous NaHCO3 (500 mL), brine (1 L), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide 14 (106 g, 91%) as a pale yellow oil; 1H NMR (300 MHz, CDCl3) δ 7.70-7.40 (m, 2H), 7.00 (d, J=8.8 Hz, 1H), 3.56 (br s, 3H), 3.35 (br s, 3H); ESI MS m/z 262 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:22])[N:7]2[C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.ClC1C=CC=C(Cl)C=1N1C2C(=C(C3C=CC(F)=CC=3F)C=C([O:51]C)C=2)CCC1=O>>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:2]1[CH2:11][C:10]([OH:51])([O:12][CH3:13])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:22])[N:7]2[C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21]
Reactant: COc1cc(Br)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Reactant: COc1cc(-c2ccc(F)cc2F)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Reactant: OB(O)c1ccccc1Cl
Product: COC1(O)C=C2C(=C(c3ccccc3Cl)C1)CCC(=O)N2c1c(Cl)cccc1Cl

Procedure:
5-(2-Chlorophenyl)-1-(2,6-dichlorophenyl)-3,4-dihydro-7-hydroxy-7-methoxy-2(1H)-quinolinone was prepared from 5-bromo-1-(2,6-dichlorophenyl)-3,4-dihydro-7-methoxy-2(1H)-quinolinone (INTERMEDIATE 1) and 2-chlorophenylboronic acid by a procedure analogous to that described in INTERMEDIATE 2. Mass spectrum (ESI) 434.0 (M+1). 1H NMR (500 MHz, CDCl3): δ 7.43-7.54 (m, 2H); 7.30-7.42 (m, 4H) 6.48 (d, J=2.5 Hz, 1H); 5.82 (d, J=2.5 Hz, 1H); 5.89 (d, J=2.5 Hz, 1H); 3.69 (s, 3H); 2.63-2.88 (m, 4H).
Reaction SMILES: O[CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=2)[C:11]([NH2:13])=[O:12])[N:6]=[N:5][N:4]=1.S(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[Cl:23][CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=2)[C:11]([NH2:13])=[O:12])[N:6]=[N:5][N:4]=1
Reactant: NC(=O)c1cc(-n2nnnc2CO)cc(C(F)(F)F)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: NC(=O)c1cc(-n2nnnc2CCl)cc(C(F)(F)F)c1
Yield: 67.7 %

Procedure:
To a suspension of 3-[5-(hydroxymethyl)-1H-tetrazol-1-yl]-5-(trifluoromethyl)benzamide (500 mg, 1.741 mmol) in toluene (5 mL) was added thionyl chloride (0.140 mL, 1.92 mmol) and the reaction heated to reflux for 4 hours. The reaction was allowed to cool and the solvent removed under vacuum. The residue was partitioned between DCM (20 mL) and water (10 mL). The organic layer collected via a hydrophobic frit and the solvent removed under vacuum. The residue was purified by silica chromatography (Biotage SP4, eluting 10% EtOAc in iso-hexane (5 column volumes) then a gradient from 10-100% EtOAc in iso-hexane (over 10 column volumes)) to yield the title compound as a pale yellow gum (360 mg).
Reaction SMILES: [O:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][OH:9])[N:3]=[CH:2]1.CCN(CC)CC.[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C(Cl)Cl>[Si:21]([O:9][CH2:8][CH2:7][CH2:6][C:4]1[N:3]=[CH:2][O:1][CH:5]=1)([C:18]([CH3:20])([CH3:19])[CH3:17])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCc1cocn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCc1cocn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
To a sol. of 3-oxazol-4-yl-propan-1-ol (1.14 g, 8.96 mmol) in dry CH2Cl2 (25 mL) at 0° C. were added Et3N (3.12 mL, 22.4 mmol) and TBDMS-Cl (2.02 g, 13.4 mmol). The reaction mixture was stirred at rt overnight, and the mixture was concentrated under reduced pressure. The residue was diluted in Et2O, and the mixture was washed with water. The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (heptane/Et2O; 30:1→1:1) yielded the title compound (1.84 g, 85%). LC-MS: tR=1.06, ES+: 242.28.
Reaction SMILES: S([O-])([O-])=O.C1C(C(N)=O)=CN(C2OC(COP(OP(OCC3OC(N4C5N=CN=C(N)C=5N=C4)C(OP([O-])([O-])=O)C3O)([O-])=O)([O-])=O)C(O)C2O)C=C1.[Na+:53].[Na+:54].[Na+].[Na+].[C:57]1([C:76]([OH:78])=[O:77])[C:66]2[C:65]([C:67]([OH:69])=[O:68])=[CH:64][CH:63]=[C:62]([C:70]([OH:72])=[O:71])[C:61]=2[C:60]([C:73]([OH:75])=[O:74])=[CH:59][CH:58]=1>>[Na:53][Na:54].[C:57]1([C:76]([OH:78])=[O:77])[C:66]2[C:65]([C:67]([OH:69])=[O:68])=[CH:64][CH:63]=[C:62]([C:70]([OH:72])=[O:71])[C:61]=2[C:60]([C:73]([OH:75])=[O:74])=[CH:59][CH:58]=1
Reactant: [Na+]
Agent: NC(=O)C1=CN(C2OC(COP(=O)([O-])OP(=O)([O-])OCC3OC(n4cnc5c(N)ncnc54)C(OP(=O)([O-])[O-])C3O)C(O)C2O)C=CC1
Agent: O=C(O)c1ccc(C(=O)O)c2c(C(=O)O)ccc(C(=O)O)c12
Agent: O=S([O-])[O-]
Product: [Na][Na]

Procedure:
The process as claimed in claim 6, wherein, after the oxidation has ended the reaction mixture is subjected to a heat treatment at a temperature of between 90° and 120° C. under the autogenous pressure of 1 to 10 bar which is established, in the presence of sulfite, the resulting suspension of the tetrasodium salt of naphthalene-1,4,5,8-tetracarboxylic acid is cooled, after the reaction vessel has been let down, to a temperature of below 40° C. the pH is then adjusted to 4.5 to 5 by acidification, the resulting disodium salt of naphthalene-1,4,5,8-tetracarboxylic acid is isolated, this salt is converted into the tetrasodium salt of naphthalene-1,4,5,8-tetracarboxylic acid in an aqueous alkali metal hydroxide solution and, optionally after removal of insoluble impurities, naphthalene-1,4,5,8-tetracarboxylic acid 1,8-monoanhydride is precipitated by acidification to a pH of less than 2 at a temperature of 80° to 100° C.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11](Br)=[N:10][N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[OH:21])[C:8]2=[O:22])=[CH:4][CH:3]=1.[CH3:25][O-:26].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([O:26][CH3:25])=[N:10][N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[OH:21])[C:8]2=[O:22])=[CH:4][CH:3]=1
Reactant: O=c1c(Br)nn(-c2ccccc2O)c(=O)n1Cc1ccc(Cl)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nn(-c2ccccc2O)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 26.1 %

Procedure:
According to Scheme 9 Step 2: To a solution of 4-(4-chlorobenzyl)-6-bromo-2-(2-hydroxyphenyl)-1,2,4-triazine-3,5(2H,4H)-dione (0.130 g, 0.32 mmol) in DMF (3 ml) was added, dropwise, at 0° C. a solution 2M of sodium methoxide (0.32 mmol, 0.160 ml). The mixture was stirred 1 h at 0° C. 1 more equivalent of a solution 2M of sodium methoxide was necessary to complete the conversion. Then the reaction mixture was quenched with water. The aqueous layers was neutralised till pH=7 and extracted with ethyl acetate (×3). The organic layer were combined and successively washed with water then, brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography, 10 g prepacked column, DCM/MeOH 98/2 to afford (30 mg, Yield=26%) 30 mg (Yield=26%) of 4-(4-chlorobenzyl)-2-(2-hydroxyphenyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione 4.143 were recovered as a white solid.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[S:3][CH:2]=1.C(O[C:15](=O)[NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23](=[O:28])N(OC)C)[CH2:19][CH2:18]1)(C)(C)C.[O:30]=[C:31]1[NH:36][C:35]2[CH:37]=[C:38](C=O)[CH:39]=[CH:40][C:34]=2[S:33][CH2:32]1>>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[S:3][C:2]=1[C:23]([C@H:20]1[CH2:19][CH2:18][C@H:17]([NH:16][CH2:15][C:38]2[CH:39]=[CH:40][C:34]3[S:33][CH2:32][C:31](=[O:30])[NH:36][C:35]=3[CH:37]=2)[CH2:22][CH2:21]1)=[O:28]
Reactant: O=Cc1ccc2c(c1)NC(=O)CS2
Reactant: c1cnc2scnc2c1
Reactant: CON(C)C(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Product: O=C1CSc2ccc(CN[C@H]3CC[C@H](C(=O)c4nc5cccnc5s4)CC3)cc2N1

Procedure:
Using thiazolo[5,4-b]pyridine (10 mmol; Synthesis (1974), 120), [trans-4-(methoxy-methyl-carbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester (5 mmol) and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbaldehyde (0.38 mmol) according to the same protocol as that described for example 1, steps 1.a to 1.c, the title compound was obtained as its hydrochloride salt (20 mg).
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[H-].[Na+].IC.[C:16](OCC)(=O)C>CN(C)C=O>[F:1][CH2:2][CH2:3][N:4]([CH3:16])[C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCCF
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(CCF)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
Under nitrogen atmosphere, tert-butyl (2-fluoroethyl)carbamate (I-286) (2 g, 20.1 mmol) was dissolved in N,N-dimethylformamide (50 ml), then sodium hydride (55%, w/w) (803 mg, 18.4 mmol) was added to the solution at 0° C., followed by stirring at 0° C. for 30 minutes. After 30 minutes, iodomethane (1.2 ml, 19.7 mmol) was added, followed by stirring at room temperature for 19 hours. Ethyl acetate was added to the reaction liquid, followed by washing with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated away under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=3:1, v/V) to obtain the entitled compound (970 mg, 45%) as a white crystal.
Reaction SMILES: [O:1]=[C:2]([C:8]1[S:9][CH:10]=[CH:11][N:12]=1)[CH2:3][C:4]([O:6]C)=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1>C1(C)C(C)=CC=CC=1>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([NH:21][C:4](=[O:6])[CH2:3][C:2](=[O:1])[C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: COc1cccc(N)c1
Reactant: COC(=O)CC(=O)c1nccs1
Solvent: Cc1ccccc1C
Product: COc1cccc(NC(=O)CC(=O)c2nccs2)c1
Reaction time: 6 h

Procedure:
To 30 mL of a xylene solution containing 2.3 g of methyl 3-oxo-3-(1,3-thiazol-2-yl)propionate, 1.4 mL of m-anisidine was added. The reaction mixture was stirred for 6 hours under reflux by heating. The solvent was removed under reduced pressure, and water and ethyl acetate were added thereto. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 3.3 g of a brown oily substance, N-(3-methoxyphenyl)-3-oxo-3-(1,3-thiazol-2-yl)propaneamide.