Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[CH3:5][CH:6]([CH2:8][C:9]([CH3:11])=[O:10])[CH3:7].[CH3:12]C(C)=O>>[OH:3][C:2]1[CH:4]=[CH:7][C:6]2[C:5](=[CH:12][CH:11]=[C:9]([OH:10])[CH:8]=2)[CH:1]=1
Reactant: CC(=O)CC(C)C
Reactant: CC(C)=O
Product: Oc1ccc2cc(O)ccc2c1

Procedure:
Sixty parts by weight of acetone was added to 100 parts by weight of the oily phase containing the oxidation product obtained in Example 8, (1) to prepare an MIBK/acetone mixed oily phase which was subjected to acid cleavage by the following method to obtain 2,6-dihydroxynaphthalene.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C@@H:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8]1)=[O:6])[CH3:3].C>O>[CH2:2]([O:4][C:5]([C@@H:7]1[CH2:15][CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[NH:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)[C@@H]1Cc2ccccc2N1
Agent: Cl
Solvent: O
Product: CCOC(=O)[C@@H]1CC2CCCCC2N1

Procedure:
The (2S)-2-ethoxycarbonylindoline hydrochloride obtained is hydrogenated in solution in 150 ml of water in the presence of 2 g of palladinised charcoal for 8 hours at 45° C. under 50 kg/cm2 pressure.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(N(C(C)C)C(C)C)C.[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([O:41][CH3:42])=[C:36]([CH:40]=1)[C:37](Cl)=[O:38]>C1C=CC=CC=1>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([O:41][CH3:42])=[C:36]([CH:40]=1)[C:37]([N:7]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:38]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: CCOC(=O)CCCNc1ccccc1-c1ccccc1
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCN(C(=O)c1cc(Cl)ccc1OC)c1ccccc1-c1ccccc1
Yield: 94 %

Procedure:
Analogously to Example 47, 10.0 g of ethyl 4-(biphenyl-2-yl)aminobutyrate and 4.6 g of ethyldiisopropylamine in 50 ml of benzene are reacted with a solution of 7.3 g of 5-chloro-2-methoxybenzoyl chloride in 20 ml of benzene to obtain, as reaction product, 15.0 g (94.1% of theory) of ethyl 4-[5-chloro-2-methoxy-N-(biphenyl-2-yl)benzamido]butyrate as a viscous non-distillable oil. The saponification of this ester yields 12.4 g (88% of theory) of 4-[5-chloro-2-methoxy-N-(biphenyl-2-yl)benzamido-9 butyric acid, MP 160° to 162°.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:17]([CH3:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=3[O:20][CH3:21])[N:7]([CH2:22][C:23]([O:25]C(C)C)=[O:24])[C:6]=2[C:5]([CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>CO>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:17]([CH3:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=3[O:20][CH3:21])[N:7]([CH2:22][C:23]([OH:25])=[O:24])[C:6]=2[C:5]([CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[CH:4][CH:3]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Nc3c(C)cc(Cl)cc3OC)n(CC(=O)OC(C)C)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3c(C)cc(Cl)cc3OC)n(CC(=O)O)c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.9 %

Procedure:
To a solution of isopropyl [4-chloro-2-[(4-chloro-2-methoxy-6-methylphenyl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]acetate (Reference Example 11; 861 mg, 1.75 mmol) in methanol (5 mL) was added 8N aqueous sodium hydroxide (1.5 mL), and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, followed by neutralization with 6N hydrochloric acid. The mixture was concentrated in vacuo, and the residue was dissolved in methanol. The precipitate was removed by filtration, and the filtrate was concentrated in vacuo to give the title compound (781 mg, 1.73 mmol, 99.1%) as an amorphous.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:9]([C:10](O)=[O:11])=[CH:8][C:7]([C:13]([NH2:15])=[O:14])=[C:6]([O:16][CH3:17])[CH:5]=1)#[N:2].[NH2:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=1>C(O)(=O)C>[OH:11][C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:16][CH3:17])=[C:7]([C:13]([NH2:15])=[O:14])[CH:8]=2)[CH:3]=[C:1]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:2]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: COc1cc(CC#N)c(C(=O)O)cc1C(N)=O
Solvent: CC(=O)O
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(O)c2cc1C(N)=O
Temperature: 130 °C
Yield: 85.9 %

Procedure:
A mixture of 6-Cyanomethyl-4-methoxy-isophthalamic acid (0.5 g, 2.34 mmol), 3-amino-5-methylpyrazol (0.45 g, 4.68 mmol), acetic acid (10 ml) were sealed in microwave process vial (20 ml). The mixture was heated at 130° C. for 30 minutes under microwave irradiation. After removal of acetic acid, the residue was dissolved in 1.5 ml MeOH. This solution was added dropwise to 30 ml water, and the formed solid was collected and purified by flash column chromatography to give product (0.63 g, 86%). LC-MS: m/e 314 (MH+).
Reaction SMILES: [C:1]([OH:12])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][N:14]([CH3:19])[CH2:15][CH2:16][CH2:17]O>>[C:1]([O:12][CH2:17][CH2:16][CH2:15][N:14]([CH3:19])[CH3:13])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CN(C)CCCO
Product: CCCCCCC/C=C/C(=O)OCCCN(C)C

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 3-dimethylamino-1-propanol as starting materials to give the aimed compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]([CH2:8][C:9](O)=[O:10])[C:6](=[O:12])[C:5]([NH:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)(=[O:16])=[O:15])=[CH:4][CH:3]=1.Br.Br.[S:30]1[C:34]2[CH2:35][CH:36]([NH2:39])[CH2:37][CH2:38][C:33]=2[N:32]=[C:31]1[NH2:40]>>[NH2:40][C:31]1[S:30][C:34]2[CH2:35][CH:36]([NH:39][C:9](=[O:10])[CH2:8][N:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]([NH:13][S:14]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:19]=4)(=[O:15])=[O:16])[C:6]3=[O:12])[CH2:37][CH2:38][C:33]=2[N:32]=1
Reactant: Nc1nc2c(s1)CC(N)CC2
Reactant: Cc1ccc(NS(=O)(=O)Cc2cccc(C(F)(F)F)c2)c(=O)n1CC(=O)O
Agent: Br
Product: Cc1ccc(NS(=O)(=O)Cc2cccc(C(F)(F)F)c2)c(=O)n1CC(=O)NC1CCc2nc(N)sc2C1

Procedure:
The title compound was prepared from 2-[6-methyl-2-oxo-3-({[3-(trifluoromethyl)benzyl]sulfonyl}amino)-1(2H)-pyridinyl]acetic acid and 4,5,6,7-tetrahydro-1,3-benzothiazol-2,6-diamine dihydrobromide using the procedure of EXAMPLE 1 (STEP 6), and was obtained as a white solid compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]2[CH2:12][CH:11]([C:13]3[O:17][NH:16][C:15](=[O:18])[CH:14]=3)[CH2:10][CH2:9][N:8]2[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])=[N:5][N:4]=[N:3]1.CCCCCCC.CCO>C(#N)C>[CH3:1][N:2]1[C:6]([C@H:7]2[CH2:12][C@@H:11]([C:13]3[O:17][NH:16][C:15](=[O:18])[CH:14]=3)[CH2:10][CH2:9][N:8]2[C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1C1CC(c2cc(=O)[nH]o2)CCN1C(=O)OCc1ccccc1
Solvent: CCO
Solvent: CC#N
Solvent: CCCCCCC
Product: Cn1nnnc1[C@H]1C[C@@H](c2cc(=O)[nH]o2)CCN1C(=O)OCc1ccccc1
Yield: 47.3 %

Procedure:
Benzyl 2-(1-methyl-1H-tetrazol-5-yl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (488 mg, 1.27 mmol) was subjected to chiral preparative HPLC (Column: Chiralpak AS (250×20), 5 μm particle size, mobile phase: Heptane/EtOH/DEA 60/40/0.1, flow rate 18 mL/min) to yield (2R,4S)-benzyl 2-(1-methyl-1H-tetrazol-5-yl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (231 mg, 47%), chiral purity 98% ee, Optical rotation [α]D20=+14.5 (acetonitrile, c=1)
Reaction SMILES: [Cl:1][C:2]([Cl:11])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[I:12]I.CCCCCC.CCOCC>C(Cl)(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[I:12][C:8]1[CH:9]=[C:5]([C:3](=[O:4])[C:2]([Cl:1])([Cl:10])[Cl:11])[NH:6][CH:7]=1
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: O=C(c1cc(I)c[nH]1)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
The title compound was prepared from 2-(trichloroacetyl)pyrrole according to the method of Bélanger, Tetrahedron Lett., 1979, 2505. Thus, iodine (12.0 g, 47.2 mmol) was added portionwise (approximately 1 g per portion) over 0.17 h to a magnetically stirred mixture of silver trifluoroacetate (11.0 g, 49.8 mmol) and 2-(trichloroacetyl)pyrrole (10.0 g, 47.1 mmol) in dry chloroform (70 ml) maintained at 0° C. (ice-bath). After addition was complete the reaction mixture was allowed to warm to 18° C. and stirred at this temperature for a further 2 h. The resultant suspension was filtered through a sintered glass funnel (No. 3 porosity) and the filtrate washed with Na2S2O5 (1×80 ml of 5% w/v aqueous solution) and water (2×80 ml) then dried (MgSO4), filtered and concentrated under reduced pressure. The solid residue thus obtained was treated with hexane/ether (50 ml of a 4:1 v/v mixture) and the resulting suspension stirred at 18° C. for 5 h then the solid was filtered off to give the title compound (13.1 g, 82%) as a cream solid, m.p. 129-130° C. (lit. m.p. 128-130° C.). 1H n.m.r. d 9.45, broad s, 1H; 7.44, dd, J 2.6 and 1.3 Hz, 1H; 7.19, dd, J 2.6 and 1.3 Hz, 1H.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]3[CH:22]=[CH:23][CH:24]=[C:18]3[CH:17]1[CH2:25][C:26]([OH:28])=O)(=[O:15])=[O:14])[CH:7]=[CH:6]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:62]([NH:66][CH2:67][C:68]1[CH:69]=[C:70]2[C:75](=[CH:76][CH:77]=1)[CH2:74][CH:73]([NH2:78])[CH2:72][CH2:71]2)([CH3:65])([CH3:64])[CH3:63]>C(Cl)Cl>[C:62]([NH:66][CH2:67][C:68]1[CH:69]=[C:70]2[C:75](=[CH:76][CH:77]=1)[CH2:74][CH:73]([NH:78][C:26](=[O:28])[CH2:25][CH:17]1[N:16]([S:13]([C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:9]=3)(=[O:14])=[O:15])[CH2:21][CH2:20][N:19]3[CH:22]=[CH:23][CH:24]=[C:18]13)[CH2:72][CH2:71]2)([CH3:65])([CH3:63])[CH3:64]
Reactant: COc1ccc2cc(S(=O)(=O)N3CCn4cccc4C3CC(=O)O)ccc2c1
Reactant: CC(C)(C)NCc1ccc2c(c1)CCC(N)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc2cc(S(=O)(=O)N3CCn4cccc4C3CC(=O)NC3CCc4cc(CNC(C)(C)C)ccc4C3)ccc2c1
Reaction time: 0.5 h
Yield: 34 %

Procedure:
To a cooled (0° C.) suspension of 2-(2-(6-methoxynaphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid (S2) (310 mg, 0.77 mmol, 1.0 eq.) in DCM (20 ml) was added HATU (600 mg, 1.54 mmol, 2 eq.) and DIPEA (0.4 ml, 2.31 mmol, 3 eq.) and the reaction mixture was allowed to stir for 30 min. Finally, 6-((tert-Butylamino)methyl)-1,2,3,4-tetrahydronaphthalen-2-amine (A15) (180 mg, 0.77 mmol, 1.0 eq.) was added and the reaction mixture and it was stirred at RT for 16 h. The mixture was diluted with DCM (100 ml) and successively washed with ammonium chloride solution (50 ml), sodium bicarbonate solution (50 ml), water (10 ml) and brine (10 ml). The organics were dried over Na2SO4 and the solvent was evaporated under reduced pressure to give the crude product which was purified by column chromatography (silica gel, 6% MeOH/DCM) to yield the pure title compound as a white solid. Yield: 34% (160 mg, 0.26 mmol); MS, Rt=3.6 min; m/z=615.1 [MH]+
Reaction SMILES: [C:1]1([CH:7]([C:11](=O)[CH3:12])[C:8](=O)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:14]([C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][OH:24])[CH:19]=[CH:20][CH:21]=1)[NH2:15].Cl>>[CH3:12][C:11]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:8]([CH3:9])[N:14]([C:16]2[CH:17]=[C:18]([CH2:22][CH2:23][OH:24])[CH:19]=[CH:20][CH:21]=2)[N:15]=1
Reactant: NNc1cccc(CCO)c1
Reactant: CC(=O)C(C(C)=O)c1ccccc1
Agent: Cl
Product: Cc1nn(-c2cccc(CCO)c2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from 3-phenyl-2,4-pentanedione and 2-(3-hydrazinophenyl)ethanol (WO 94/07896) hydrochloride: MS (ESI) m/z 293 [M+H]+, 1H-NMR (CDCl3) δ 7.44-7.22 (9H, m), 3.87 (2H, t, J=6.0 Hz), 2.67 (2H, t, J=6.0 Hz), 2.33 (3H, s), 2.15 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]=[CH:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[CH2:20][CH2:19][CH2:18][C:12]=3[C:13](=[O:17])[NH:14][C:15]=2[CH:16]=1)=[O:4].[Mg]>CO.C1COCC1>[CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:11]3[CH2:20][CH2:19][CH2:18][CH:12]3[C:13](=[O:17])[NH:14][C:15]=2[CH:16]=1)=[O:4]
Reactant: COC(=O)C=Cc1ccc2c3c(c(=O)[nH]c2c1)CCC3
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CCc1ccc2c(c1)NC(=O)C1CCCC21
Temperature: 25 °C
Reaction time: 24 h
Yield: 22 %

Procedure:
A solution of 550 mg (2.0 mmol) of 7-(methoxycarbonyl-ethenyl)-1,2,3,5-tetrahydrocyclopenta[c]quinolin-4-one in 130 ml of methanol-THF 3:1 is mixed with 972 mg (40.0 mmol) of magnesium and stirred for 24 hours at room temperature. The reaction mixture is filtered over glass fibers, the filter residue is washed with dichloromethane-methanol, and the combined filtrates are concentrated by evaporation in a vacuum. Purification of the residue on silica gel yields 120 mg of product.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:22]3[CH:27]=[CH:26][C:25]([N:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=3)[C:18]3[C:13](=[CH:14][C:15]([N:19]([CH3:21])[CH3:20])=[CH:16][CH:17]=3)[C:11](=[O:12])[O:10]2)=[CH:5][CH:4]=1.CN(C)C1C=C(C=CC=1)C(O)=O.NC1C=C(C=CC=1)C(O)=O.CI.[OH-].[K+].CN(C)C1C=CC(C(O)C2C=CC(N(C)C)=CC=2)=CC=1.S(=O)(=O)(O)O>>[CH3:30][N:28]([CH3:29])[C:25]1[CH:26]=[CH:27][C:22]([CH:9]([C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:31])[CH3:1])=[CH:8][CH:7]=2)[C:18]2[CH:17]=[CH:16][C:15]([N:19]([CH3:20])[CH3:21])=[CH:14][C:13]=2[C:11]([OH:12])=[O:10])=[CH:23][CH:24]=1
Reactant: CN(C)c1ccc(C2(c3ccc(N(C)C)cc3)OC(=O)c3cc(N(C)C)ccc32)cc1
Agent: CN(C)c1ccc(C(O)c2ccc(N(C)C)cc2)cc1
Agent: CN(C)c1cccc(C(=O)O)c1
Agent: Nc1cccc(C(=O)O)c1
Solvent: CI
Product: CN(C)c1ccc(C(c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2C(=O)O)cc1

Procedure:
U.S. Pat. No. 2,417,897 and its corresponding U.S. Pat. No. Re. 23,024, which issued Mar. 25, 1947 and Aug. 17, 1948, respectively, disclose a three-step process for the preparation of 3,3-bis(4-dimethylaminophenyl)-6-dimethylaminophthalide, Crystal Violet Lactone (CVL). In the first step, 3-dimethylaminobenzoic acid is prepared from 3-aminobenzoic acid by alkylating the free amine using methyl iodide in the presence of potassium hydroxide. In the second step, the 3-dimethylaminobenzoic acid is condensed with 4,4'-bis(dimethylamino)benzhydrol in the presence of sulfuric acid to obtain 2-[bis(4-dimethylaminophenyl)methyl]-5-dimethylaminobenzoic acid. In the third step, the 2-[bis(4-dimethylaminophenyl)methyl]-5-dimethylaminobenzoic acid is oxidized using lead dioxide in dilute hydrochloric acid to obtain the CVL.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[N:15][N:16]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:17]=3[CH:18]=[CH:19][CH:20]=2)=[O:11])[CH:5]=[CH:4][NH:3]1.[C:28]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C.O>[CH3:28][N:3]1[CH:4]=[CH:5][C:6]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[N:15][N:16]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:17]=3[CH:18]=[CH:19][CH:20]=2)=[O:11])=[CH:7][C:2]1=[O:1]
Reactant: O=C(NCc1cc[nH]c(=O)c1)c1cccc2c1cnn2-c1ccc(F)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: Cn1ccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)cc1=O
Temperature: 60 °C

Procedure:
To a stirred solution of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid (2-oxo-1,2-dihydro-pyridin-4-ylmethyl)-amide (50 mg, 0.1 mmol) in DMF (1.0 mL) was added K2CO3 (45.8 mg, 0.331 mmol) followed by iodomethane (0.017 mL, 0.28 mmol). The mixture was warmed at 60° C. for 3 hours. The mixture was diluted with water (10 mL), and a white solid was obtained by filtration. The solid was washed with water (5×10 mL) and air dried. The resulting solid was purified by silica gel chromatography eluting with a gradient of 0-5% MeOH in CH2Cl2 to afford the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:16]3[CH:17]=[C:18]4[O:23][CH2:22][O:21][C:19]4=[CH:20][C:15]=3[CH2:14][C:13]([CH3:24])=[N:12][N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O)C.Cl.[BH4-].[Na+]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:16]3[CH:17]=[C:18]4[O:23][CH2:22][O:21][C:19]4=[CH:20][C:15]=3[CH2:14][CH:13]([CH3:24])[NH:12][N:11]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC1=NN=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2C1)OCO3
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1)OCO3
Reaction time: 0.25 h
Yield: 97.2 %

Procedure:
To a suspension of 5.0 g (15.5 mmol) of the known 1-(4-nitrophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (French patent specification No. 85,09793) in 380 ml of ethanol first 22.5 ml (0.278 mol) of concentrated hydrochloric acid were added at constant stirring whereupon a solution was formed within a few minutes, then 11.5 g (0.3 mole) of sodium borohydride were charged into the solution portionwise during 30 minutes. Stirring was continued for 15 minutes, then the orange-coloured precipitate formed was filtered and extracted on the filter with 4×30 ml of chloroform. The combined chloroform filtrate was evaporated under reduced pressure, the crystalline residue was brought to a filter with 200 ml of distilled water, then washed with 3×20 ml of distilled water and dried at 80°-100° C. to yield 4.90 g (97.2%) of the aimed product, m.p.: 162°-164° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=2[C:12]([O:14]C)=[O:13])[CH2:3]1.[C:21]1([C:27]2[O:28][C:29]([CH3:34])=[C:30]([CH2:32]I)[N:31]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:10]([CH2:9][O:8][CH:4]2[CH2:5][CH2:6][CH2:7][CH:2]([O:1][CH2:32][C:30]3[N:31]=[C:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[O:28][C:29]=3[CH3:34])[CH2:3]2)[C:11]=1[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1c(C)cccc1COC1CCCC(O)C1
Reactant: Cc1oc(-c2ccccc2)nc1CI
Product: Cc1cccc(COC2CCCC(OCc3nc(-c4ccccc4)oc3C)C2)c1C(=O)O

Procedure:
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and 2-phenyl-4-iodomethyl-5-methyloxazole as starting materials in the procedure of Example XXXI, gave the product 69 of molecular weight 435.52 (C26H29NO5), MS(ESI): 436.32 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[NH:5][CH:6]([CH3:11])[CH2:7][C:8]([OH:10])=O.[C:15](Cl)([Cl:17])=[O:16].C(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12]([C:8](=[O:10])[CH2:7][CH:6]([CH3:11])[N:5]2[C:15]([Cl:17])=[O:16])=[CH:13][CH:14]=1
Reactant: CC(CC(=O)O)Nc1cccc(Cl)c1
Reactant: O=C(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1CC(=O)c2ccc(Cl)cc2N1C(=O)Cl

Procedure:
7-Chloro-1-chloroformyl-2-methyl-1,2,3,4-tetrahydro-4-quinolinone is prepared in a manner similar to that described in Example 5 but starting from 3-(3-chloroanilino)butanoic acid (5.42 g; 25.4 mmol), phosgene (6.7 g; 67.7 mmol), methylene chloride (25 cc), dimethylformamide (0.23 cc) and aluminum chloride (8.15 g; 61.1 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][CH:7]=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH2:22][CH2:23][CH2:24][F:25]>C(#N)C>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]([CH2:21][CH2:22][CH2:23][CH2:24][F:25])[CH:7]=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1
Reactant: O=S1(=O)N=CNc2ccc(Cl)cc21
Reactant: FCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=S1(=O)N=CN(CCCCF)c2ccc(Cl)cc21
Temperature: 100 °C

Procedure:
150 mg of the compound obtained in Step A of Example 1 are dissolved in 8 ml of acetonitrile, to which 300 mg of K2CO3 and 0.15 ml of 1-bromo-4-fluorobutane are added. The reaction mixture is introduced into a sealed autoclave and is heated at 100° C. for 3 hours. After cooling, the solvent is evaporated off under reduced pressure and the residue is taken up in a minimum of water. The insoluble material is collected by filtration, washed with water and dried. The precipitate is then recrystallised from a minimum of ethyl acetate with the aid of heat. After cooling, the title compound is collected by filtration, washed with a minimum of ethyl acetate and dried.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[CH2:19][CH3:20]>CN(C=O)C.CCOC(C)=O>[CH2:18]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:5][CH2:4][CH3:8])[C:5]([O:7][CH2:10][CH2:2][CH3:3])=[O:6])[CH2:19][CH3:20]
Reactant: CCCBr
Reactant: O=C(O)c1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCOC(=O)c1ccc(OCCC)c(OCCC)c1
Temperature: 55 °C
Reaction time: 8 h
Yield: 158.9 %

Procedure:
A mixture of 3,4-dihydroxybenzoic acid (0.65 g; 4.22 mmol), anhydrous K2CO3 (1.75 g; 12.7 mmol) and n-PrBr (1.5 ml; 4 mmol) in anhydrous DMF (5 ml) was stirred at ˜55° C. overnight. After cooling to room temperature, the mixture was diluted to 25 ml with EtOAc, washed with H2O (2×10 ml), brine, dried over anhydrous MgSO4, filtered and the filtrate evaporated to dryness to give the title compound (0.94 g; 80%), as heavy syrup, which was used in next step without further purification. 1H-NMR (CDCl3) 0.97-1.04 (m, 9H); 1.7-1.9 (m, 6H); 3.97-4.02 (m, 4H); 4.2-4.26 (m, 2H); 6.85 (d, 1H, J=8.4 Hz); 7.53 (s, 1H); 7.62 (d, 1H, J=8.4 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:10]2[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=2)[C:13]([NH:15][C@@H:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17]2)=[O:14])=[N:6][C:7]=1[C:8]#[N:9].C(Cl)Cl.[C:31](O)([C:33](F)(F)F)=O>CN1C(=O)CCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:10]2[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=2)[C:13]([NH:15][C@@H:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17]2)=[O:14])=[N:6][C:7]=1[C:8]1[NH:3][C:2]([C@H:31]2[CH2:33][CH2:4][CH2:5][NH:6][CH2:7]2)=[N:1][N:9]=1
Reactant: N#Cc1nc(-c2cccc(C(=O)N[C@H]3CCc4ccccc43)c2)cnc1N
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: Nc1ncc(-c2cccc(C(=O)N[C@H]3CCc4ccccc43)c2)nc1-c1nnc([C@H]2CCCNC2)[nH]1

Procedure:
A solution of 3-(5-amino-6-cyanopyrazine-2-yl)-N-[(1S)-2,3-dihydro-1H-inden-1-yl]benzamide (2.4 g, 6.6 mmol) and 1,1-dimethyl (3S)-3-(hydrazinocarbonyl)piperidine-1-carboxylate (2.4 g, 10.1 mmol) in NMP (3 mL) was heated to 180-200° C. for 1 h. The solvent was removed under reduced pressure. The residue obtained was stirred with CH2Cl2/TFA (20% v/v)) for 30 min., concentrated and purified by hplc. The compound was converted to the hydrochloride salt using a 4 M solution of HCl in dioxane to afford 3-(5-amino-6-{5-[(3S)-piperidin-3-yl]-4H-1,2,4-triazol-3-yl}pyrazin-2-yl)-N-[(1S)-2,3-dihydro-1H-inden-1-yl]benzamide: 1H NMR (400 MHz; CD3OD): 8.65 (s, 1H); 8.6 (d, 1H); 7.6 (t, 1H); 7.7-7.8 (m, 4H); 5.7 (t, 1H); 3.75-3.4 (m, 4H); 3.8-3.36 (m, 3H); 3.35-2.8 (m, 3H); 2.6 (m, 1H); 2.4 (m, 2H); 2.1-2.0(m, 4H); 1.3 (t, 3H); MS (EI) for C27H28N8O: 481 (MH+).
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9]C)[CH:5]=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12]>C(O)(=O)C.Br.CCOCC.C([O-])(O)=O.[Na+]>[F:1][C:2]1[C:7]([CH3:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12]
Reactant: COc1ccc(C(C)=O)c(F)c1C
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(=O)c1ccc(O)c(C)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
A solution of 1.09 g (5.96 mmol) 1-(2-fluoro-4-methoxy-3-methyl-phenyl)-ethanone was dissolved in 12 ml acetic acid and 6 ml 62% aqueous HBr. The reaction mixture was stirred 2 h at room temperature and heated to 120° C. for 6 h, cooled, diluted with ether and neutralized carefully with aqueous saturated NaHCO3 (pH=8). Extraction of the water phase with ether (two times), washing with aqueous 10% NaCl, drying (Na2SO4) and evaporation gave 0.78 g of the crude product as a dark red gum.