Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl[CH2:34][C:35]([N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)=[O:36]>[Cu]I.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:34][C:35]([N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[O:36])[C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C(CCl)N1CCCCC1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CN1CCc2c(n(CC(=O)N3CCCCC3)c3ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 3.9 %

Procedure:
The title compound was prepared by following general procedure 7. 9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.43 mmol), was taken into DMF. To the above solution CuI (8 mg, 0.043 mmol), L-proline (9 mg, 0.086 mmol), K3PO4 (183 mg, 0.86 mmol) were added and stirred for 10 min. at RT. 2-Chloro-1-(piperidin-1-yl)ethanone (83 mg, 0.51 mmol) was added dropwise. The reaction mixture was heated at 90° C. for 12 h. After completion of reaction, the reaction mixture was filtered through Celite. DMF was evaporated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure to obtain 6 mg of 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(piperidin-1-yl)ethanone as the TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.C([N:24]=[C:25]=[S:26])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:25]([NH2:24])=[S:26])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (500 mg, 2.46 mmol) in THF (30 ml) at 0° C. was slowly added benzoyl isothiocyanate (0.366 ml, 2.583 mmol) and the reaction mixture was stirred at rt for 2 hours. The solvents were evaporated and the residue was dissolved in methanol (50 ml). A solution of potassium carbonate (1.02 g, 7.38 mmol) in water (23 ml) was added dropwise at rt, the reaction mixture was stirred for 3 h at rt. The methanol was evaporated, water (10 ml) was added and stirred at rt for 1 hour. The solids were filtered off, washed with diethyl ether and dried in vacuo. After trituration with diethyl ether the title compound was obtained as light yellow solid (490 mg, 76%). MS ISP (m/e): 263.1 (100) [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].C(N(C(C)C)C(C)C)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>ClCCl.C(#N)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:17]=[C:2]([NH:1][S:43]([CH3:42])(=[O:45])=[O:44])[CH:3]=[CH:4][C:5]=2[NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:11][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2ccc(N)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nc1ccc(NCC2CCNCC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Reaction time: 8 h
Yield: 55.2 %

Procedure:
A suspension of 5-amino-N-(5-chloropyridin-2-yl)-2-[(1-Boc-piperidin-4-yl)methylamino]benzamide (0.55 g, 1.2 mmol) in 12 mL of dichloromethane at 0° C. was treated with ethyldiisopropylamine (231 μL, 1.3 mmol) followed by methanesulfonyl chloride (93 μL, 1.2 mmol). The reaction mixture was allowed to reach room temperature overnight, then it was concentrated in vacuo to a crude residue. The residue was directly applied to an SCX column, which was washed with methanol and allowed to stand overnight. Elution with 1:1 dichloromethane-1 N ammonia in methanol provided yellow fractions, which were combined and concentrated in vacuo to a crude residue. Purification by silica gel chromatography, eluting with 9:1 dichloromethane-2 N ammonia in methanol, afforded solid material which was taken up in acetonitrile and sonicated for several minutes. The resulting suspension was filtered, giving rise to the title compound (0.29 g, 56%) as a pale-yellow solid.
Reaction SMILES: N#N.C([O:6][C:7]([C:9]1[N:10]=[CH:11][O:12][C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][CH:22]([CH3:24])[CH3:23])[CH:15]=1)=[O:8])(C)C.[OH-].[Na+].Cl>C1COCC1>[CH:22]([O:21][CH2:20][C:16]1[CH:15]=[C:14]([C:13]2[O:12][CH:11]=[N:10][C:9]=2[C:7]([OH:8])=[O:6])[CH:19]=[CH:18][CH:17]=1)([CH3:24])[CH3:23]
Reactant: CC(C)OCc1cccc(-c2ocnc2C(=O)OC(C)C)c1
Agent: Cl
Agent: N#N
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)OCc1cccc(-c2ocnc2C(=O)O)c1
Reaction time: 1.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(3-isopropoxymethyl-phenyl)-oxazole-4-carboxylic acid isopropyl ester (78 mg, 0.26 mmol) in THF (2.5 mL) was treated with a 1N NaOH (1.3 mL). The resulting mixture was stirred for 1.5 h then acidified with 1N HCl, extracted twice with EA (2×20 mL) and the combined organic phases were washed with brine (20 mL). The organic layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 02: tR=0.87 min, [M+AcCN+H]+=303.18.
Reaction SMILES: [NH:1]1[CH:5]=[C:4](/[CH:6]=[C:7]2\[C:8](=[O:33])[C:9]3[C:14]([CH2:15][CH2:16]\2)=[C:13]([O:17][CH2:18][C@H:19]2[CH2:23][CH2:22][CH2:21][N:20]2[C:24]2[N:32]=[CH:31][N:30]=[C:29]4[C:25]=2[N:26]=[CH:27][NH:28]4)[CH:12]=[CH:11][CH:10]=3)[N:3]=[CH:2]1.[OH-].[Na+]>C(O)(=O)C.O.[Zn]>[NH:1]1[CH:5]=[C:4]([CH2:6][CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[O:17][CH2:18][C@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[C:24]3[N:32]=[CH:31][N:30]=[C:29]4[C:25]=3[N:26]=[CH:27][NH:28]4)[C:8]2=[O:33])[N:3]=[CH:2]1
Reactant: O=C1/C(=C\c2c[nH]cn2)CCc2c(OC[C@H]3CCCN3c3ncnc4[nH]cnc34)cccc21
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2cccc(OC[C@H]3CCCN3c3ncnc4[nH]cnc34)c2CCC1Cc1c[nH]cn1

Procedure:
13.5 100 mg of 2-[1-(1H-imidazol-4-yl)meth-(Z)-ylidene]-5-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-ylmethoxy]-3,4-dihydro-2H-naphthalen-1-one are heated at 80° C. for 30 min. together with 50 mg of zinc powder in 10 ml of conc. acetic acid and 5 ml of water. During this, the colour changes from greenish to yellowish. The batch is adjusted to pH 7 using conc. NaOH solution and extracted to exhaustion with ethyl acetate. The organic phase is dried over magnesium sulfate and freed from solvent in vacuo, giving 50 mg of 2-(1H-imidazol-4-yl-methyl)-5-[(R)-1-(9H-purin-6-yl)pyrrolidin-2-ylmethoxy]-3,4-dihydro-2H-naphthalen-1-one (“A15.1”) as colourless oil. Rt.: 1.405 min; [M+H]+444.2.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:11]=2[C:12]=1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([N:30]([CH2:35][CH3:36])[CH2:31][CH2:32][CH2:33]Cl)[CH3:29]>>[CH2:1]([C:8]1[O:9][C:10]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:11]=2[C:12]=1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:33][CH2:32][CH2:31][N:30]([CH2:35][CH3:36])[CH2:28][CH3:29])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CCCCl
Reactant: O=S(=O)(c1ccc(O)cc1)c1c(Cc2ccccc2)oc2ccc(Br)cc12
Product: CCN(CC)CCCOc1ccc(S(=O)(=O)c2c(Cc3ccccc3)oc3ccc(Br)cc23)cc1

Procedure:
Reaction of 2-benzyl-5-bromo-3-(4-hydroxyphenylsulfonyl)benzofuran with 3-diethylaminopropyl chloride as previously described gives the title compound.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([O:14][C:15](=[O:21])/[CH:16]=[CH:17]\[C:18]([OH:20])=[O:19])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[CH:22]1([NH:28][CH2:29][CH2:30][CH2:31][NH2:32])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>O1CCOCC1>[CH2:11]1[CH2:10][CH2:9][CH:8]([O:14][C:15](=[O:21])[C@H:16]([CH2:17][C:18]([OH:20])=[O:19])[NH:32][CH2:31][CH2:30][CH2:29][NH:28][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:13][CH2:12]1
Reactant: O=C(O)/C=C\C(=O)OC1CCCCC1
Reactant: NCCCNC1CCCCC1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(O)C[C@H](NCCCNC1CCCCC1)C(=O)OC1CCCCC1
Yield: 85.2 %

Procedure:
400 ml of triethylamine are added dropwise to a solution of 433.8 g (2 mols+10% excess) of maleic acid-monocyclohexyl ester and 200 ml of dioxane, in a manner analogous to that of Example 1, and the mixture is then reacted with 310.5 g (2.0 mols) of 3-cyclohexylamino-1-propylamine for 40 minutes at 70°-90° C. The reaction mixture is further processed as in Example 1 to yield 604 g (85.2% of theory) of a white crystalline aspartic acid derivative, which decomposes at 172°-173° C.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH3:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[H][H].C1(C)C=CC=CC=1>CO.Cl>[OH:1][C@H:2]([CH2:8][CH2:9][CH3:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: CCCC(=O)CC(=O)OC
Reactant: [H][H]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: CCC[C@@H](O)CC(=O)OC

Procedure:
Methyl 3-ketohexanoate (44.7 g, 310 mmol) was diluted with methanol (75 mL) and 0.2N HCl (2 mL). Et2NH2 +Ru2Cl5- (BINAP)2 (200 mg) was added and the mixture was heated at 60° under 100 psi of hydrogen for 2 hours. Toluene (100 mL) was added and the mixture was concentrated to an oil weighing 75 g.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[CH3:13][C:14](=[CH:16][CH2:17][CH2:18]/[C:19](=[CH:21]/[CH2:22]O)/[CH3:20])[CH3:15].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH2:22]/[CH:21]=[C:19](\[CH3:20])/[CH2:18][CH2:17][CH:16]=[C:14]([CH3:15])[CH3:13])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: CC(=O)c1ccccc1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)c1ccccc1C(=O)OC/C=C(\C)CCC=C(C)C
Reaction time: 75 h
Yield: 77.5 %

Procedure:
A solution of 6.49 g (39.0 mmol) 2-acetylbenzoic acid, 3.81 g (31.2 mmol) DMAP and 12.32 g (80.0 mmol) geraniol in 60 ml dichloromethane was cooled in an ice bath before adding a solution of 8.84 g (42.9 mmol) DCC in 40 ml dichloromethane for 5 min. The reaction mixture was maintained with stirring at 40° for 75 h. The precipitate formed during the reaction was filtered and the filtrate washed with HCl (10%, 2×) and with a saturated Na2CO3 solution (2×). The organic phase was dried (Na2SO4) and concentrated. The excess geraniol was distilled, and the residue chromatographed (SiO2, 9:1 toluene/ethyl acetate) to give 9.08 g (78%) of the desired compound in the form of a slightly yellow oil.
Reaction SMILES: C(O[C:4]1[CH2:8][CH2:7][CH2:6][N:5]=1)C.[CH3:9][CH:10]([CH:12]1[CH2:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[CH2:13]1)[CH3:11]>C(O)(C)C>[CH3:11][CH:10]([CH:12]1[CH2:13][C:14](=[O:19])[C:15](=[C:4]2[CH2:8][CH2:7][CH2:6][NH:5]2)[C:16](=[O:18])[CH2:17]1)[CH3:9]
Reactant: CCOC1=NCCC1
Reactant: CC(C)C1CC(=O)CC(=O)C1
Solvent: CC(C)O
Product: CC(C)C1CC(=O)C(=C2CCCN2)C(=O)C1
Reaction time: 8 h
Yield: 12.4 %

Procedure:
A mixture of 2-ethoxy-1-pyrroline (9.05 grams, 0.08 mole), and 5-(1-methylethyl)-1,3-cyclohexanedione (12.34 grams, 0.08 mole), in 50 mL of isopropyl alcohol solvent is heated under reflux for 2 hours. After standing overnight, the cooled reaction solution will deposit white, crystalline product which is collected, washed with cold solvent and dried to give 2.2 grams of solid, m.p. 143°-145° C. The filtrate is evaporated and the residue dissolved in dichloromethane and the solution extracted with three portions of 3N NaOH followed by three portions of 3N hydrochloric acid. Addition of 3N NaOH to the acid solution causes precipitation of an 0.87-gram portion of product, m.p. 143.5°-145° C. The latter is recrystallized from ethyl acetate for an analytical sample.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[C:2]1C=CC=CC=1.[C:20](OC[C@H]1OC1)(=[O:24])CCC>>[OH:24][CH2:20][C@H:1]1[O:8][C:9](=[O:19])[N:10]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[CH2:2]1
Reactant: COc1ccc(NC(=O)OCc2ccccc2)cc1
Reactant: CCCC(=O)OC[C@@H]1CO1
Product: COc1ccc(N2C[C@@H](CO)OC2=O)cc1

Procedure:
Starting from (4-methoxy-phenyl)-carbamic acid benzyl ester (prepared from 4-methoxy-aniline and CbzCl according to procedure C) and (S)-glycidyl butyrate and following the procedure described for the preparation of intermediate 1.iii), the title compound was obtained as a grey solid (469 mg, 54%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@H:9]([NH:21][CH2:22][C:23]3[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=3)[CH2:10][C@H:11]([CH3:20])[N:12]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=1[O:37][CH3:38])=[O:4].N1C=CC=CC=1.Cl[C:46]([O:48][CH3:49])=[O:47]>ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@H:9]([N:21]([CH2:22][C:23]3[CH:24]=[C:25]([C:33]([F:34])([F:36])[F:35])[CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=3)[C:46]([O:48][CH3:49])=[O:47])[CH2:10][C@H:11]([CH3:20])[N:12]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=1[O:37][CH3:38])=[O:4]
Reactant: CCOC(=O)N1c2cc(C(=O)OC)c(OC)cc2[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)N1c2cc(C(=O)OC)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 135.1 %

Procedure:
cis-4-(3,5-Bis-trifluoromethyl-benzylamino)-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1,7-dicarboxylic acid 1-ethyl ester 7-methyl ester (335 mg, 0.61 mmol) was dissolved in anhydrous dichloromethane (5 mL), and pyridine (0.20 mL, 2.5 mmol) was added. Methyl chloroformate (0.057 mL, 0.73 mmol) was slowly added and the reaction was stirred at room temperature for 3 h. Additional aliquots of reagents were added to drive the reaction to completion. The reaction mixture was then diluted with 35 ml dichloromethane, washed with an aqueous 1N HCl solution (2×7 mL) and with a saturated sodium bicarbonate solution (2×7 mL) saturated NaHCO3. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography using 20% acetone/hexanes as eluent afforded the title product (0.50 g, 90%). MS m/z 607 (M++1); 1H NMR (CDCl3) δ 1.5-1.75 (br, 1H), 6.42 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([OH:11])=[C:6]([NH:12][S:13]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])(=[O:15])=[O:14])[CH:5]=1.Br[CH2:27][CH2:28]Br>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([F:10])[C:7]2[O:11][CH2:28][CH2:27][N:12]([S:13]([C:16]3[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=3[O:23][CH3:24])(=[O:15])=[O:14])[C:6]=2[CH:5]=1)=[O:25]
Reactant: COC(=O)c1cc(F)c(O)c(NS(=O)(=O)c2cc(Cl)ccc2OC)c1
Reactant: BrCCBr
Product: COC(=O)c1cc(F)c2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CCO2

Procedure:
The title compound, MS (ISP)=519.1 (M−H)−, was produced in analogy with example 36, steps 1-4. Step 1 was performed using 3-(5-chloro-2-methoxy-benzenesulfonylamino)-5-fluoro-4-hydroxy-benzoic acid methyl ester (example 44, step 2) and 1,2-dibromoethane, yielding 4-(5-chloro-2-methoxy-benzenesulfonyl)-8-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester, which was hydrolyzed in step 2 to afford 4-(5-chloro-2-methoxy-benzenesulfonyl)-8-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid. This was reacted with ethyl 4-aminobenzoate in step 3 to produce 4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-8-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 4.
Reaction SMILES: [OH:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]=[C:3]1[C:12]([F:15])([F:14])[F:13].CI.[C:18](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:18][O:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]=[C:3]1[C:12]([F:15])([F:14])[F:13]
Reactant: On1c(C(F)(F)F)nc2ncc(Cl)cc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COn1c(C(F)(F)F)nc2ncc(Cl)cc21

Procedure:
1-Hydroxy-6-chloro-2-(trifluoromethyl)-1H-imidazo-(4,5-b)pyridine (5 grams), 80 milliliters of acetone, 5 milliliters of methyl iodide, and 10 grams of anhydrous potassium carbonate were mixed, heated and refluxed with stirring for twelve hours. The reaction mixture was then filtered, evaporated and eluted off of a silica column with diethyl ether, yielding the desired 1-methoxy-6-chloro-2-(trifluoromethyl)-1H-imidazo(4,5-b)pyridine product. It was recrystallized from petroleum ether (boiling at 60°-80°C.). The product so obtained melted at 91°-2°C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([N+:16]([O-])=O)[C:8]([CH3:15])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:16][C:7]1[C:8]([CH3:15])=[C:9]([CH:14]=[C:5]([O:4][CH2:3][CH2:2][OH:1])[CH:6]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1cc(OCCO)cc([N+](=O)[O-])c1C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1cc(OCCO)cc(N)c1C
Temperature: 80 °C
Yield: 98.2 %

Procedure:
To a stirred solution of methyl 5-(2-hydroxyethoxy)-2-methyl-3-nitrobenzoate (1.5 g, 5.88 mmol) in ethanol (20 mL), were added ammonium chloride (1.5 g, 28 mmol) dissolved in water (20 mL) and iron powder (1.3 g, 23 mmol). The resulting reaction mixture was heated at 80° C. for 3 h. On completion, the reaction mixture was filtered and the residue washed well with hot ethanol. The filtrate was concentrated and the residue was basified by aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with water, dried, and concentrated under reduced pressure giving the crude title compound (1.3 g) which was used directly.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[OH:3][C:4]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:7]
Reactant: O=C(O)c1ccc(O)cc1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)c1ccc(O)cc1O
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To a solution of 3 g (0.1 mole) of sodium hydride (80% in oil) and 50 ml of dimethylformamide (DMF), there are slowly added 15.4 g (0.1 mole) of 2,4-dihydroxybenzoic acid dissolved in 50 ml of DMF. The mixture is stirred at ambient temperature until the cessation of gaseous emission. There are then added 13.1 ml (0.1 mole) of benzyl bromide and the mixture is stirred at ambient temperature until solubilization of the reaction medium. The reaction mixture is poured into water, and extracted with ethyl ether. The organic phase is decanted, washed with water, dried on magnesium sulfate and evaporated. The residue is purified by chromatography on a silica column by eluting with dichloromethane. 19.7 g (81% yield) of the expected ester having a melting point of 94°-95° C. are recovered.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:3]=1[C:4]1[O:5][C:6]2[C:11]([C:12](=[O:15])[C:13]=1[CH3:14])=[CH:10][CH:9]=[CH:8][C:7]=2[C:16]([OH:18])=[O:17].[OH-].[Na+:25]>CO>[CH3:1][C:2]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:3]=1[C:4]1[O:5][C:6]2[C:11]([C:12](=[O:15])[C:13]=1[CH3:14])=[CH:10][CH:9]=[CH:8][C:7]=2[C:16]([O-:18])=[O:17].[Na+:25]
Reactant: Cc1ccc(-c2oc3c(C(=O)O)cccc3c(=O)c2C)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2oc3c(C(=O)[O-])cccc3c(=O)c2C)c(C)c1

Procedure:
One gram of 2',3,4'-trimethylflavone-8-carboxylic acid prepared by the same way as Example 1 is dissolved in methanol, equimolar 2N sodium hydroxide solution is added thereto, methanol is evaporated therefrom, the residue is dissolved in small amount of water, the solution is lyophilized, and 1.0 gram of sodium 2',3,4'-trimethylflavone-8-carboxylate, colorless powder, melting point 218° to 220° C., is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH2:17][CH:18]3[O:20][CH2:19]3)[C:15](=[O:21])[N:14]([CH3:22])[C:13](=[O:23])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][CH2:19][CH:18]([OH:20])[CH2:17][N:16]1[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:12][C:13](=[O:23])[N:14]([CH3:22])[C:15]1=[O:21])([CH3:27])([CH3:26])[CH3:25]
Reactant: COc1ccc(-c2cc(=O)n(C)c(=O)n2CC2CO2)cc1OC
Reactant: CC(C)(C)N
Product: COc1ccc(-c2cc(=O)n(C)c(=O)n2CC(O)CNC(C)(C)C)cc1OC

Procedure:
To a solution of 6-(3,4-dimethoxyphenyl)-1-(2,3-epoxypropyl)-3-methyl-2,4(1H,3H)-pyrimidinedione (0.6 g) in ehtanol (20 ml) was added tert-butylamine (2 ml). The mixture was refluxed for 2.5 hours and evaporated in vacuo. The resulting syrup was triturated in a mixture of diethyl ether and diisopropyl ether to give 1-(3-tert-butylamino-2-hydroxy-1-propyl)-6-(3,4-dimethoxyphenyl)-3-methyl-2,4(1H,3H)pyrimidinedione (0.66 g).
Reaction SMILES: OO.[F:3][CH:4]([F:29])[S:5]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[F:17])[C:10]([C:18]2[N:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([O:26][CH3:27])[N:19]=2)=C1O)(=[O:7])=[O:6].C(=O)([O-])[OH:31].[K+].N1C=CC=CC=1C(O)=O.S([O-])([O-])=O.[Na+].[Na+]>O.C(#N)C.C(#N)C.O.S([O-])([O-])(=O)=O.[Fe+2].O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2]>[CH3:27][O:26][C:20]1[N:21]=[C:22]([O:24][CH3:25])[N:23]=[C:18]([C:10]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([F:17])[C:16]=2[NH:8][S:5]([CH:4]([F:29])[F:3])(=[O:7])=[O:6])=[O:31])[N:19]=1
Reactant: COc1nc(OC)nc(-c2c(O)n(S(=O)(=O)C(F)F)c3c(F)cccc23)n1
Reactant: O=C([O-])O
Agent: [Fe+2]
Agent: O=C(O)c1ccccn1
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC#N
Product: COc1nc(OC)nc(C(=O)c2cccc(F)c2NS(=O)(=O)C(F)F)n1
Temperature: 35 °C
Reaction time: 2.83 h

Procedure:
Variant A (Oxidation with Hydrogen Peroxide and Iron Sulfate in Water/Acetonitrile): 1-[(Difluoromethyl)sulfonyl]-3-(4,6-dimethoxy-1,3,5-triazin-2-yl)-7-fluoro-1H-indol-2-ol (100 g) is initially charged in 330 ml of acetonitrile and the suspension is heated to 35° C. A solution of potassium hydrogencarbonate (25.4 g) in 145 ml of water is added dropwise within 45 min. Iron(II) sulfate heptahydrate (395 mg) and pyridine-2-carboxylic acid (175 mg) are premixed in 1 ml of water and added to the mixture. Hydrogen peroxide (35% in water, 58 g) is added dropwise over 135 min, and the internal temperature is kept at 25° C.-28° C. Stirring is continued for 170 min, sodium sulfite (3 g) and potassium hydrogencarbonate (3 g) is added, the mixture is concentrated to 282 g at 40° C. under reduced pressure, and the solid residue is filtered off. 2-Propanol (150 ml) is added to the solution and the pH is adjusted to 2 with hydrochloric acid, such that a solid precipitates out. After adding 160 ml of water, the solid is filtered off, washed with 100 ml of 2-propanol/water (1:4) and 200 ml of water, and dried. This gives N-{2-[(4,6-dimethoxy-1,3,5-triazin-2-yl)carbonyl]-6-fluorophenyl}-1,1-difluoromethanesulfonamide in a purity of 97% (86.2 g, 90% of theory).