Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([CH3:28])([CH3:27])[C:17](=[O:26])[N:18]2[CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:14][CH:13]=1>>[CH:21]1([N:18]2[C:19]3[C:15](=[CH:14][CH:13]=[C:12]([NH:11][C:4](=[O:6])[C:3]4[CH:7]=[CH:8][N:9]=[CH:10][C:2]=4[F:1])[CH:20]=3)[C:16]([CH3:27])([CH3:28])[C:17]2=[O:26])[CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CC1(C)C(=O)N(C2CCCC2)c2cc(N)ccc21
Reactant: O=C(O)c1ccncc1F
Product: CC1(C)C(=O)N(C2CCCC2)c2cc(NC(=O)c3ccncc3F)ccc21

Procedure:
Prepared in analogy to example 26 from 3-fluoroisonicotinic acid and 6-amino-1-cyclopentyl-3,3-dimethyl-1,3-dihydro-indol-2-one. The title compound was obtained as yellow foam.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=1>C(Cl)Cl>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:18])[NH:7][C:3]2[CH:2]=[C:1]([CH:6]=[CH:5][CH:4]=2)[NH2:8])=[CH:12][CH:11]=1
Reactant: Nc1cccc(N)c1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: Nc1cccc(NC(=O)Nc2ccc(Cl)cc2)c1
Reaction time: 2 h

Procedure:
m-Phenylenediamine (10.8 g.) is dissolved in methylene chloride (500 ml.) at room temperature and a solution of p-chlorophenyl isocyanate (15.35 g.) in methylene chloride (50 ml.) is added dropwise with vigorous stirring. The mixture is stirred for 2 hours after the addition is complete, and the product is filtered off, washed with methylene chloride and dried. This solid thus obtained is crystallized from methanol (3 1.) to give 3-(3-p-chlorophenylureido)aniline, which slowly decomposes on heating to 310° C. without melting, but is analytically pure.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([O:14][C:15](=[O:26])[CH2:16][CH2:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)([CH3:13])([CH3:12])[CH3:11].Cl>C(N(CC)CC)C>[C:10]([O:14][C:15](=[O:26])[CH2:16][CH2:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:21][CH:20]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)CCSc1ccc(N)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCSc1ccc(NC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (3.3 ml) and benzoyl chloride (2.0 ml) were added to the compound prepared in Example 1 and the reaction solution was stirred for 30 minutes at room temperature. 1 N hydrochloric acid was added to the reaction solution. The reaction solution was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate, water, a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with ether to give the title compound (5.17 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.CS([CH2:14][C:15]#[C:16][CH:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:21]=[CH:20][C:19]2[CH:28]=[CH:29][CH:30]=[CH:31][C:18]1=2)(=O)=O>ClCCl>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:14][C:15]#[C:16][CH:17]2[C:18]3[CH:31]=[CH:30][CH:29]=[CH:28][C:19]=3[CH:20]=[CH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]2=3)[CH2:6][CH2:5]1
Reactant: OCCN1CCNCC1
Reactant: CS(=O)(=O)CC#CC1c2ccccc2C=Cc2ccccc21
Solvent: ClCCl
Product: OCCN1CCN(CC#CC2c3ccccc3C=Cc3ccccc32)CC1

Procedure:
This preparation illustrates methods of preparing cyclic amine derivatives of formula A. In this preparation 1 gram of N-β-hydroxyethyl-piperazine is added to a solution containing 0.31 g. of 5-(3-methanesulfonylprop-1-ynyl)-5H-dibenzo[a,d]cycloheptene, according to Example 3, in 20 ml. of dichloromethane at 0°C. The resulting mixture is monitored by thin-layer chromatographic analysis and allowed to stand at room temperature until conversion of the sulfonate ester is essentially complete. The mixture is then worked up and purified according to the procedure described in Example 4, yielding 5-[3-(N'-β-hydroxyethyl-1-piperazinyl)prop-1-ynyl]-5H-dibenzo[a,d]cycloheptene.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=2[OH:11])[CH2:3][CH2:2]1.ClC1C=CC=CC=1Cl.CC(C)([O-])C.[K+].[OH:26][C:27]1[CH:32]=[C:31]([Cl:33])[N:30]=[N:29][C:28]=1Cl>C(O)(C)(C)C>[Cl:33][C:31]1[N:30]=[N:29][C:28]([O:11][C:5]2[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]2[CH2:3][CH2:2]2)=[C:27]([OH:26])[CH:32]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: Cc1cccc(C2CC2)c1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: Clc1ccccc1Cl
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
To a mixture of 1.34 g (9.05 mmol) of 2-cyclopropyl-6-methylphenol and 1,2-dichlorobenzene (7.00 mL) was added 1.20 g (9.05 mmol) of 85% potassium t-butoxide at room temperature. The resultant mixture was heated to 180° C. and subjected to azeotropic dehydration under reflux while stirring for 30 minutes. To the resultant solution was added dropwise the preliminarily prepared solution of 4.97 g (purity: 96.0%; 2.89 mmol) of 4-hydroxy-3,6-dichloropyridazine in t-butanol (35.0 g) at 170° C. over 2 hours. (The t-butanol was distilled off simultaneously with the dropwise addition of the solution.) After stirring at 180° C. for another 2 hours, the reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 701 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 88%) and 6.9 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.9%) were obtained.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].Br[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:21][C:20](=[O:22])[N:19]([C:23]3[CH:24]=[C:25]([CH:34]=[CH:35][C:36]=3[Cl:37])[CH2:26][NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[N:18]=2)=[CH:13][CH:12]=1>C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[F:1][C:2]([F:6])([F:5])[CH2:3][O:4][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:21][C:20](=[O:22])[N:19]([C:23]3[CH:24]=[C:25]([CH:34]=[CH:35][C:36]=3[Cl:37])[CH2:26][NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:30])[CH3:31])[N:18]=2)=[CH:13][CH:12]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(CBr)cc3)[nH]c2=O)c1
Reactant: OCC(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(COCC(F)(F)F)cc3)[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 294.5 %

Procedure:
To a solution of 2,2,2-trifloro ethanol (0.042 g, 0.410 mmol) in THF was added NaH (0.017 g, 0.041 mmol) at 10° C. and continued stirring at RT for 1 h. Then solution of N-(3-(3-(4-(bromomethyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)-4-chlorobenzyl)pivalamide (Intermediate-103, 0.100 g, 0.041 mmol) in THF and TBAI (0.004 g, 0.0012 mmol) were added to the reaction mixture. The reaction mass was refluxed for 2-3 h. The reaction mass was quenched in ice and pH adjusted to 6-7 and extracted with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 0.060 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 1.12 (s, 9H), 4.11-4.17 (m, 2H), 4.28 (d, J=5.4 Hz, 2H), 4.71 (s, 2H), 7.28 (d, J=9.0 Hz, 1H), 7.41 (s, 1H), 7.46 (d, J=7.8 Hz, 2H), 7.57 (d, J=8.1 Hz, 1H), 7.85 (d, J=8.1 Hz, 2H), 8.18 (t, 1H); MS (m/z): 497.31 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:38])[CH:13]([C:20]2[N:21]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[N:22]=[C:23]3[C:28]=2[CH:27]=[C:26]([F:29])[C:25]([F:30])=[CH:24]3)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:7]([F:39])[CH:6]=1)C.[OH-].[Li+]>C1COCC1.CO>[Cl:37][C:34]1[CH:33]=[CH:32][C:31]([N:21]2[C:20]([CH:13]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]3)[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:40])=[O:3])=[CH:6][C:7]=3[F:39])=[O:38])=[C:28]3[C:23]([CH:24]=[C:25]([F:30])[C:26]([F:29])=[CH:27]3)=[N:22]2)=[CH:36][CH:35]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(c2c3cc(F)c(F)cc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NC(=O)C(c2c3cc(F)c(F)cc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(F)c1

Procedure:
In analogy to the procedure described in example 7.2, [rac]-4-{2-[2-(4-chloro-phenyl)-5,6-difluoro-2H-indazol-3-yl]-2-cyclohexyl-acetylamino}-3-fluoro-benzoic acid ethyl ester was treated with 1 N aqueous lithium hydroxide solution in THF and MeOH to give the title compound as colorless oil. MS: m/e=542.3 [M+H+].
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([C:15]1[C:16]([CH2:47][OH:48])=[C:17]([C:21]3[CH:22]=[C:23]([NH:29][C:30]4[N:35]=[CH:34][C:33]([CH:36]5[CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37]5)=[CH:32][CH:31]=4)[C:24](=[O:28])[N:25]([CH3:27])[CH:26]=3)[CH:18]=[CH:19][CH:20]=1)[CH2:8]2)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[NH:38]1[CH2:37][CH:36]([C:33]2[CH:32]=[CH:31][C:30]([NH:29][C:23]3[C:24](=[O:28])[N:25]([CH3:27])[CH:26]=[C:21]([C:17]4[C:16]([CH2:47][OH:48])=[C:15]([N:9]5[CH2:8][C:7]6[C:11](=[CH:12][CH:13]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[CH:6]=6)[C:10]5=[O:14])[CH:20]=[CH:19][CH:18]=4)[CH:22]=3)=[N:35][CH:34]=2)[CH2:39]1
Reactant: Cn1cc(-c2cccc(N3Cc4cc(C(C)(C)C)ccc4C3=O)c2CO)cc(Nc2ccc(C3CN(C(=O)OC(C)(C)C)C3)cn2)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(-c2cccc(N3Cc4cc(C(C)(C)C)ccc4C3=O)c2CO)cc(Nc2ccc(C3CNC3)cn2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.9 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 117e (495 mg, 0.761 mmol), methylene chloride (3 mL) and trifluoroacetic acid (3 mL), and the mixture was stirred at room temperature for 3 h. After this time, the reaction mixture was concentrated, and the resulting residue was partitioned between 10% aqueous potassium carbonate (10 mL) and methylene chloride (20 mL). The layers were separated, and the aqueous phase was extracted with methylene chloride (20 mL). The organic extracts were combined, dried over sodium sulfate and filtered, and the solvent was removed under reduced pressure. The resulting residue was purified by column chromatography to afford a 25% yield (104 mg) of 117 as a white solid: mp 185-186° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.54 (s, 1H), 8.10 (s, 1H), 7.71 (d, 2H, J=8.5 Hz), 7.66 (d, 1H, J=8.5 Hz), 7.61 (d, 1H, J=8.0 Hz), 7.49 (t, 1H, J=8.0 Hz), 7.44 (d, 1H, J=6.5 Hz), 7.37 (m, 2H), 7.28 (d, 1H, J=8.5 Hz), 4.94 (s, 2H), 4.88 (t, 1H, J=4.5 Hz), 4.34 (d, 2H, J=4.5 Hz), 3.71 (m, 3H), 3.59 (s, 3H), 3.54 (m, 2H), 1.33 (s, 9H); MS (ESI+) m/z 550.2 (M+H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[O:14][C@H:11]1[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[C:20]([Si:24]([CH3:27])([CH3:26])Cl)([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C.C(OCC)(=O)C>[Si:24]([O:13][CH2:12][C@@H:11]1[O:14][C@H:10]1[CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:27])[CH3:26]
Reactant: OC[C@@H]1O[C@H]1COCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1O[C@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
2.15 g of (2S,3S)-4-benzyloxy-2,3-epoxy-1-butanol was dissolved in 13 ml of dry DMF, and 1.83 g of imidazole and 2 g of tert-butyldimethylchlorosilane were added thereto. The mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed sequentially with cold 1N hydrochloric acid, water and a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=10/1) to obtain 2.3 g of (2S,3S)-4-benzyloxy-2,3-epoxy-1-butanol tert-butyldimethylsilyl ether as colorless oily substance.
Reaction SMILES: [C:1]([C:3]1[CH:43]=[CH:42][C:6]([CH2:7][C@@:8]2([CH3:41])[N:12]3[C:13]([S:16]([N:19]4[CH2:23][CH2:22][CH2:21][C@H:20]4[C:24]([NH:26][C@H:27](C)[C:28](O)=[O:29])=[O:25])(=[O:18])=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:32]3[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([Cl:39])[CH:33]=3)[C:9]2=[O:40])=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:45]CC(N)=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[C:28]([CH2:27][NH:26][C:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:19]1[S:16]([C:13]1[N:12]2[C@@:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:43][CH:42]=3)([CH3:41])[C:9](=[O:40])[N:10]([C:32]3[CH:33]=[C:34]([Cl:39])[CH:35]=[C:36]([Cl:38])[CH:37]=3)[C:11]2=[N:15][CH:14]=1)(=[O:17])=[O:18])=[O:25])(=[O:29])[NH2:45]
Reactant: C[C@@H](NC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)O
Reactant: NCC(N)=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(S(=O)(=O)N3CCC[C@H]3C(=O)NCC(N)=O)n21
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
(S)-1-[(R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonyl]-pyrrolidine-2-carboxylic acid (see Example 5) (0.25 g, 0.435 mmol) was dissolved in a mixture of CH2Cl2 (10 mL) and DMF (0.2 mL). To this solution, were added glycinamide hydrochloride (0.072 g, 0.653 mmol), TBTU (0.21 g, 0.653 mmol), and DIPEA (0.19 mL, 1.087 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with CH2Cl2 and washed with 1N HCl followed by saturated aq. NaHCO3. The organic phase was dried over Na2SO4 and concentrated. The crude product was purified by silica gel preparative thin layer chromatography using CH2Cl2-MeOH (95:5) as an eluent to afford 0.155 g of the title compound as a white foam (M+1, 630).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[NH:8][N:7]=1)=[O:5])C.[OH-].[Na+].Cl>O1CCOCC1>[CH:11]([C:9]1[NH:8][N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=1)([CH3:13])[CH3:12]
Reactant: CCOC(=O)c1cc(C(C)C)[nH]n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)c1cc(C(=O)O)n[nH]1
Temperature: 50 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
5-Isopropyl-1H-pyrazol-3-carboxylic acid ethyl ester (18.9 g, 104 mmol) and 1M NaOH solution (260 ml, 259 mmol) were dissolved in 1,4-dioxan (300 ml), the reaction was heated to 50° C. under nitrogen and stirred for 3 hours. The reaction mixture was cooled, adjusted to pH 2 using concentrated hydrochloric acid and the solvent was removed under reduced pressure. The residual solid was azeotroped with toluene (2×30 ml), dissolved in ethyl acetate (500 ml) and washed with water (200 ml). The aqueous phase was removed, extracted with ethyl acetate (2×200 ml) and the combined organic extracts were dried over MgSO4. The solvent was removed under reduced pressure and the residue was azeotroped with dichloromethane (2×50 ml) to give 5-isopropyl-1H-pyrazol-3-carboxylic acid (14.7 g) as a white solid. 1H NMR (400 MHz, DMSO-D6): δ=12.50-13.30 (2H, brs), 6.42 (1H, s), 2.84-2.94 (1H, quin), 1.15-1.19 (6H, d) ppm. LRMS (electrospray) m/z [M−H]+ 153.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][C:16]=1[NH:17][C:18](=[O:20])[CH3:19])[C:7]([CH2:9][CH2:10][C:11](O)=[O:12])=O)([O-:3])=[O:2].O.[NH2:22][NH2:23]>C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([C:7]2[CH2:9][CH2:10][C:11](=[O:12])[NH:22][N:23]=2)[CH:14]=[CH:15][C:16]=1[NH:17][C:18](=[O:20])[CH3:19])([O-:3])=[O:2]
Reactant: CC(=O)Nc1ccc(C(=O)CCC(=O)O)cc1[N+](=O)[O-]
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(C2=NNC(=O)CC2)cc1[N+](=O)[O-]

Procedure:
32.5 gm of 3-(3'-nitro-4'-acetylamino-benzoyl)-propionic acid were added toa solution of 32.5 gm of hydrazine hydrate in 180 ml of glacial acetic acid, and the mixture was heated on a steam bath. After cooling, the precipitate formed thereby was suction-filtered off and washed with ether,yielding the desired compound; m.p. 223° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=O)[CH:5]=1.[F:13][C:14]([F:50])([F:49])[C:15]1[CH:16]=[C:17]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:18][N:19]([C:36]1[N:37]=[N:38][N:39]([CH3:41])[N:40]=1)[C@H:20]1[CH2:26][CH2:25][CH2:24][NH:23][C:22]2[CH:27]=[C:28]([C:32]([F:35])([F:34])[F:33])[C:29]([CH3:31])=[CH:30][C:21]1=2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCCl.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:23]2[CH2:24][CH2:25][CH2:26][C@H:20]([N:19]([CH2:18][C:17]3[CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=[C:15]([C:14]([F:13])([F:50])[F:49])[CH:16]=3)[C:36]3[N:37]=[N:38][N:39]([CH3:41])[N:40]=3)[C:21]3[CH:30]=[C:29]([CH3:31])[C:28]([C:32]([F:34])([F:33])[F:35])=[CH:27][C:22]2=3)[CH:5]=1
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1cccc(CN2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)c(C(F)(F)F)cc32)c1
Reaction time: 2 h
Yield: 53 %

Procedure:
Add 3-formylbenzoic acid methyl ester (133 mg, 0.815 mmol) to a solution of (S)-(3,5-bis-trifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)amine (Example 3, Step 18) (150 mg, 0.272 mmol) in acetic acid (1 mL) and 1,2-dichloroethane (10 mL) at room temperature under nitrogen and stir for 2 h. Add sodium triacetoxy borohydride (231 mg, 1.08 mmol) and stir for 3 h. Dilute the mixture with methylene chloride (30 mL) and wash with saturated aqueous sodium bicarbonate solution (2×10 mL). Extract the combined aqueous washes with methylene chloride (20 mL) and wash the combined organic extracts with brined (20 mL) and dry over anhydrous sodium sulfate. Remove the solvents under reduced pressure and purify the residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:2), to provide the title compound as a white solid (101 mg, 53%): mp 62-65° C. dec; 1H NMR (CDCl3, 300 MHz) δ 1.50-1.70 (m, 2H), 2.07-2.25 (m, 2H), 2.29 (s, 3H), 2.73-2.85 (m, 1H), 2.95-3.09 (m, 1H), 3.89 (s, 3H), 4.18 (s, 3H), 4.31-4.40 (m, 2H), 4.81-5.02 (m, 2H), 6.93 (s, 1H), 7.31-7.42 (m, 2H), 7.55-7.63 (m, 4H), 7.79-7.82 (m, 1H), 7.89-7.92 (m, 1H), 8.10 (s, 1H); ESI MS m/z 701 [C32H29F9N6O2+H]+; HPLC 97.6%, tR 19.7 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH3:14])[CH2:7][CH2:6]2.[BH4-].[Na+].O>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([OH:13])[CH:8]([CH3:14])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC(C)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)CCC(C)C2O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To an ice-cooled solution of 6-methoxy-2-methyl-3,4-dihydro-2H-naphthalen-1-one (7.0 g, 36.8 mmol) in MeOH (120 mL) is added NaBH4 (2.78 g, 73.6 mmol) portion wise and the mixture is stirred at RT for 20 min. Then the reaction is poured to 120 mL of water and extracted with ether. The organic phase is dried with MgSO4, concentrated to give the title compound as a light yellow oil and it is used in the next step without purification.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C:21]2[CH:49]=[CH:48][C:24]([C:25]([NH:27][C:28]3[CH:29]=[C:30]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[CH:31]=[CH:32][C:33]=3[NH:34]C(=O)OC(C)(C)C)=[O:26])=[CH:23][CH:22]=2)[CH2:17]1)=O)(C)(C)C>C(Cl)Cl>[NH2:34][C:33]1[CH:32]=[CH:31][C:30]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[CH:29][C:28]=1[NH:27][C:25](=[O:26])[C:24]1[CH:48]=[CH:49][C:21]([N:18]2[CH2:19][CH2:20][C@H:16]([NH2:15])[CH2:17]2)=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)c1ccc(N2CC[C@H](NC(=O)OC(C)(C)C)C2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(-c2ccccc2)cc1NC(=O)c1ccc(N2CC[C@H](N)C2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.5 %

Procedure:
TFA (1 mL) was added to a solution of 326 (370 mg, 0.65 mmol) in DCM (1 mL). The reaction mixture was stirred at room temperature for 24 h, concentrated and the residue was partitioned between EtOAc and NaHCO3. The aqueous layer was extracted with fresh EtOAc and the comb organic layers were washed with brine, dried over MgSO4 and concentrated. The residue was purified using the Biotage system, (cartridge Biotage Si 25+M), eluent MeOH/DCM (10% to 40%) to afford the title compound 327 (161 mg, 67% yield).
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7](CC)[CH2:8][CH2:9]CC)(=[O:4])[CH:2]=[CH2:3].C(OCCC(OC(=O)C(C)=C)C)(=O)C(C)=C.C=CC=C.C(OC)(=O)C(C)=C.C(OCCOC(=O)C(C)=C)(=O)C(C)=C>>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCC(CC)CCCC
Agent: C=C(C)C(=O)OC
Agent: C=C(C)C(=O)OCCC(C)OC(=O)C(=C)C
Agent: C=C(C)C(=O)OCCOC(=O)C(=C)C
Product: C=CC(=O)OCCCC

Procedure:
Graft-Copolymers A-5, A-6, A-7 and A-8 were prepared by the procedure of Example 18 except that a crosslinked homopolymer of 2-ethylhexyl acrylate obtained through emulsion polymerization using 1% of 1,3-butanediol dimethacrylate as the crosslinking agent, a crosslinked copolymer comprising 55% of 2-ethylhexyl acrylate, 30% of butadiene, and 15% of methyl methacrylate obtained by using 1% of ethyleneglycol dimethacrylate, a crosslinked homopolymer of butyl acrylate obtained by using 1% of 1,3-butanediol dimethacrylate as the crosslinking agent, and a crosslinked homopolymer of butadiene obtained by using 1% of divinylbenzene as the crosslinking agent were respectively used as elastomeric trunk polymers. These graft-copolymers alone are shown in Table 4 as Comparison Examples 10 through 13, all of which exhibited poor powder characteristics.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]([O:15]C(=O)C)[CH:12]=[C:11]2[C:6]=1[C:7](=[O:29])[C:8]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)=[C:9]([CH2:19]Br)[O:10]2)(=O)C.[CH3:30][NH:31][CH3:32].[ClH:33]>C(Cl)(Cl)Cl>[ClH:33].[CH3:30][N:31]([CH2:19][C:9]1[O:10][C:11]2[C:6]([C:7](=[O:29])[C:8]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)=[C:5]([OH:4])[CH:14]=[C:13]([OH:15])[CH:12]=2)[CH3:32]
Reactant: CNC
Reactant: COc1ccc(-c2c(CBr)oc3cc(OC(C)=O)cc(OC(C)=O)c3c2=O)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2c(CN(C)C)oc3cc(O)cc(O)c3c2=O)cc1
Reaction time: 1 h

Procedure:
To a solution of 5,7-diacetoxy-4'-methoxy-2-bromomethylisoflavone (500 mg) in 5 ml chloroform, was added 240 mg of 50% aqueous solution of dimethylamine at room temperature with stirring. After one hour, the solid which separated out was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:chloroform). To the liquid thus obtained was added ethanolic solution of hydrogen chloride, the solvent was distilled off, and the solid which separated out was recrystallized from ethanol, giving 150 mg of 2-(dimethylaminomethyl)-5,7-dihydroxy-4'-methoxyisoflavone hydrochloride.