Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:21]=[C:20]([C:22](O)=[O:23])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2].Cl.[OH:26][C:27]1[C:36]([CH3:37])=[CH:35][CH:34]=[C:33]2[C:28]=1[CH2:29][CH2:30][NH:31][CH2:32]2>>[C:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:21]=[C:20]([C:22]([N:31]3[CH2:30][CH2:29][C:28]4[C:33](=[CH:34][CH:35]=[C:36]([CH3:37])[C:27]=4[OH:26])[CH2:32]3)=[O:23])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: Cc1ccc2c(c1O)CCNC2
Reactant: CC(=O)NCc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Agent: Cl
Product: CC(=O)NCc1ccc(-c2nc(C(=O)N3CCc4c(ccc(C)c4O)C3)c3ccccc3n2)cc1
Yield: 13 %

Procedure:
Reaction of 2-(4-(acetamidomethyl)phenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 69 (13% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.91 (s, 3H), 2.13 and 2.17 (2s, 3H), 2.66 and 2.92 (2t, 2H), 3.49 and 4.05 (2t, 2H), 4.35-4.37 (m, 2H), 4.40 and 4.93 (2s, 2H), 6.29 and 6.74 (2d, 1H), 6.79 and 7.00 (2d, 1H), 7.42-7.47 (m, 2H), 7.68-8.11 (m, 5H), 8.43-8.46 (m, 3H); MS (ESI) m/z 467 ([M+H]+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1.[C:12]1([CH:18]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][NH2:29])[CH2:22][CH2:21]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C(C)C)C(C)C)C>C(O)CCC>[C:30]1([CH:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][NH:29][C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8](=[O:11])[NH:9][N:10]=4)[N:7]=3)[CH2:22][CH2:21]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: O=c1[nH]nc2ccc(Cl)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: O=c1[nH]nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Yield: 28.1 %

Procedure:
0.512 g of 6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one was dissolved in 15 ml of n-butanol; 0.88 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 1.04 ml of N-ethyldiisopropylamine were added, followed by refluxing under heating in an oil bath for 5 hours. After cooling, the n-butanol was mostly distilled off under reduced pressure; to the residue, an aqueous solution of sodium hydrogen carbonate was added; the reaction mixture was extracted with ethyl acetate; the extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (85:15:1). The desired fraction was collected and concentrated; the crystal obtained was filtered, washed with diethyl ether, and dried, to yield 0.35 g of the title compound.
Reaction SMILES: [C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Na+]>O>[C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)O
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
In a 1 L flask, 83.4 g of ferrous sulfate (heptahydrate) and 10.4 g of sodium nitrite were thoroughly mixed with 500 ml of distilled water, followed by 20 minutes of stirring at 40° C. Thereafter, 125 ml of concentrated ammonia was added thereto and insoluble matter was collected and washed twice with distilled water to obtain magnetite. The resulting magnetite was added to 500 ml of distilled water in a 1 L flask and the temperature of the solution was raised to 80° C. Then, 7.5 g of sodium oleate was added thereto, followed by 20 minutes of stirring at the same temperature. Thereafter, pH of the solution was adjusted to 5.5 and the resulting insoluble matter was collected by filtration and washed twice with distilled water to obtain magnetite having an oleic acid layer. The magnetite was again added into a 1 L flask, 500 ml of distilled water was added, and the temperature of the solution was raised to 70° C. Then, 7.5 g of sodium dodecylbenzenesulfonate was added thereto and the whole was stirred overnight to obtain magnetic fine particles. Using the magnetic fine particles, the magnetic fine particles of the invention to which a UCST polymer was immobilized were prepared according to the following method.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:15]3[CH2:16][CH:12]([CH2:13][NH:14]3)[CH2:11][CH:10]=2)[CH:6]=[N:7][CH:8]=1.[CH2:17]=O>C(O)=O>[CH3:17][N:14]1[CH2:13][CH:12]2[CH2:16][CH:15]1[C:9]([C:5]1[CH:6]=[N:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[CH:10][CH2:11]2
Reactant: COc1cncc(C2=CCC3CNC2C3)c1
Reactant: C=O
Solvent: O=CO
Product: COc1cncc(C2=CCC3CC2N(C)C3)c1
Yield: 56 %

Procedure:
A mixture of 4-(5-methoxy-3-pyridinyl)-6-azabicyclo[3.2.1]oct-3-ene (15 mg, 0.07 mmol), aqueous formaldehyde (37%, 0.25 mL) and 90% formic acid (1 mL) was heated at reflux for 1½ h. The mixture was concentrated under reduced pressure, and the remaining volatiles were removed by azeotropic evaporation with methanol (thee times). The residue was made basic with dilute aqueous sodium hydroxide and extracted into dichloromethane. The extracts were dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was chromatographed on a silica gel column, eluting with 90:10:1 dichloromethane/methanol/concentrated ammonium hydroxide. Concentration of selected fractions gave the product as an oil (9.0 mg, 56%).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[F:27][C:24]1[CH:25]=[C:26]2[C:21]([CH:20]=[CH:19][CH:18]=[C:17]2[CH2:16][N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[C:6]2[C:4]([OH:3])=[O:5])=[CH:22][CH:23]=1
Reactant: Fc1ccc2cccc(CBr)c2c1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Product: O=C(O)c1cc2ccccc2n1Cc1cccc2ccc(F)cc12

Procedure:
Using general procedure B, 1H-indole-2-carboxylic acid ethyl ester was coupled with 1-bromomethyl-7-fluoro-naphthalene and the product obtained was hydrolyzed to give 1-(7-fluoro-naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid as a white solid. MS: 318.0 ([M−H]).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].CCN(C(C)C)C(C)C.[Cl:21][CH:22]([CH3:26])[C:23](Cl)=[O:24].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:11][O:10][C:1](=[O:9])[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:23](=[O:24])[CH:22]([Cl:21])[CH3:26]
Reactant: CC(Cl)C(=O)Cl
Reactant: COC(=O)c1ccccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccccc1NC(=O)C(C)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
To methyl anthranilate (5 g, 33.1 mmol) stirring in DCM at 0° C. under N2 was added DIEA (5.1 g, 39.7 mmol) in one portion followed by the dropwise addition of 2-chloropropionyl chloride (4.2 g, 33.1 mmol). The reaction was allowed to stir at 0° C. for 30 min. then warmed to room temperature, stirring for an additional 3 h. The reaction was treated with saturated aqueous solution of NaHCO3 and the resulting biphasic mixture transferred to a separatory funnel. The layers separated and the aqueous layer was extracted twice more with DCM (25 mL). The combined organic layers were washed with brine, dried over MgSO4 and concentrated under vacuum to afford the desired product (7.75 g, 97% yield), which was used without further purification. 1H-NMR (CDCl3): δ 11.8 (br, 1H), 8.72 (dd, 1H), 8.08 (dd, 1H), 7.58 (m, 1H), 7.15 (m, 1H), 4.56 (q, 1H), 3.97 (s, 3H), 1.85 (d, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH2:3][CH2:2]1.N1C=CC=CC=1.[C:19](Cl)(Cl)=[O:20].[CH2:23]([C:25]1[N:30]=[C:29]([NH2:31])[CH:28]=[CH:27][C:26]=1[O:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39]2[CH:40]=[N:41][C:42]([CH3:45])=[CH:43][CH:44]=2)[CH:34]=1)[CH3:24]>C(Cl)Cl>[CH2:23]([C:25]1[N:30]=[C:29]([NH:31][C:19]([N:9]2[CH2:10][CH2:11][N:7]([CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[C:8]2=[O:12])=[O:20])[CH:28]=[CH:27][C:26]=1[O:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39]2[CH:40]=[N:41][C:42]([CH3:45])=[CH:43][CH:44]=2)[CH:34]=1)[CH3:24]
Reactant: O=C(Cl)Cl
Reactant: CCc1nc(N)ccc1Oc1ccnc(-c2ccc(C)nc2)c1
Reactant: O=C1NCCN1C1CCOCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1nc(NC(=O)N2CCN(C3CCOCC3)C2=O)ccc1Oc1ccnc(-c2ccc(C)nc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.2 %

Procedure:
A 0° C. solution of Example B1 (0.19 g, 1.116 mmol) and pyridine (0.26 mL, 3.21 mmol) in DCM (5 mL) was treated drop-wise with phosgene (20% in toluene, 1.4 mL, 2.65 mmol) and warmed to RT over 0.5 h. The mixture was treated slowly with a solution of 6-ethyl-5-((6′-methyl-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-amine (0.16 g, 0.522 mmol) and pyridine (0.16 mL, 1.978 mmol) in DCM (5 mL) and stirred at RT overnight. The mixture was treated with satd. NaHCO3, extracted with EtOAc (4×) and the combined organics were dried over MgSO4, concentrated to dryness, purified via silica gel chromatography (MeOH/DCM), then re-purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA). The combined fractions were treated with satd. NaHCO3, extracted with DCM (5×) and the combined organics were dried over MgSO4 and concentrated to dryness to afford N-(6-ethyl-5-((6′-methyl-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (19 mg, 7%). 1H NMR (400 MHz, DMSO-d6): δ 10.93 (s, 1 H), 9.09 (d, J=2.4 Hz, 1 H), 8.52 (d, J=5.7 Hz, 1 H), 8.28 (dd, J=8.1, 2.4 Hz, 1 H), 7.90 (d, J=8.8 Hz, 1 H), 7.64 (d, J=8.8 Hz, 1 H), 7.59 (d, J=2.4 Hz, 1 H), 7.33 (d, J=8.2 Hz, 1H), 6.77 (dd, J=5.7, 2.4 Hz, 1 H), 3.94-3.84 (m, 3 H), 3.83-3.79 (m, 2 H), 3.46 (t, J=8.2 Hz, 2 H), 3.38 (t, J=11.6 Hz, 2 H), 2.58 (q, J=7.5 Hz, 2 H), 2.50 (s, 3 H), 1.72 (dd, J=12.3, 4.5 Hz, 2 H), 1.62 (s, 2 H), 1.12 (t, J=7.5 Hz, 3H); MS (ESI) m/z: 503.3 (M+H+).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]([O:27]CC)=O)=[O:22])[CH2:17][CH2:16]3)=[N:13][CH:14]=2)=[CH:5][CH:4]=1.[CH3:32][NH2:33]>O1CCCC1.ClCCl.CO>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]([NH:33][CH3:32])=[O:27])=[O:22])[CH2:17][CH2:16]3)=[N:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: CN
Reactant: CCOC(=O)COC(=O)N1CCN(c2ccc(-c3ccc(C(F)(F)F)cc3)cn2)CC1
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)COC(=O)N1CCN(c2ccc(-c3ccc(C(F)(F)F)cc3)cn2)CC1

Procedure:
The process is performed according to the procedure described in Example 1 (step 1.4.). Starting with 2.77 g (6.33 mmol) of 2-(ethyloxy)-2-oxoethyl 4-{5-[4-(trifluoromethyl)phenyl]-2-pyridyl}-1-piperazine-carboxylate, obtained in step 4.1., and 15.80 ml (31.67 mmol) of a solution of methylamine (2M) in tetrahydrofuran, and after chromatography on silica gel, eluting with a 97/3 mixture of dichloromethane and methanol, followed by recrystallization from ethyl acetate, 1.69 g of product are obtained in the form of a white solid.
Reaction SMILES: C([O:8][C:9](=[O:42])[CH2:10][C@@H:11]([N:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[CH:26]1)[C:12]([NH:14][C@H:15]([C:20]1[NH:21][CH:22]=[CH:23][N:24]=1)[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13])C1C=CC=CC=1>CCO.C1COCC1>[CH:9]([OH:42])=[O:8].[NH:24]1[CH:23]=[CH:22][N:21]=[C:20]1[C@@H:15]([NH:14][C:12](=[O:13])[C@H:11]([N:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[CH:32][C:33]([C:36]3[CH:37]=[CH:38][N:39]=[CH:40][CH:41]=3)=[CH:34][CH:35]=2)=[CH:26]1)[CH2:10][C:9]([OH:42])=[O:8])[CH2:16][CH:17]([CH3:18])[CH3:19]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccncc3)cc2)c1)c1ncc[nH]1
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)C[C@H](NC(=O)[C@@H](CC(=O)O)n1ccc(-c2ccc(-c3ccncc3)cc2)c1)c1ncc[nH]1
Product: O=CO
Yield: 81 %

Procedure:
According to the procedure described in Example 7(a), N-[1(S)-(1H-imidazol-2-yl)-3-methylbutyl]-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid benzyl ester was hydrogenolyzed in EtOH:THF (1:1) to yield in 81% yield N-[1(S)-(1H-imidazol-2-yl)-3-methylbutyl]-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid formate salt as a yellow amorphous solid. 1H NMR (DMSO-d6): δ 12.30 (bs, 1H), 8.65 (d, 1H, J=8.1 Hz), 8.59 (d, 2H, J=4.4 Hz), 8.13 (s, 1H), 7.75 (d, 2H, J=8.5 Hz), 7.71 (d, 2H, J=4.4 Hz), 7.60 (d, 2H, J=8.5 Hz), 7.34 (s, 1H), 6.91-6.83 (m, 3H), 6.44 (s, 1H), 5.08 (t, 1H, J=7.5 Hz), 4.97 (dd, 1H, J=8.1, 16.2 Hz), 3.10 (dd, 1H, J=8.1, 16.6 Hz), 2.90 (dd, 1H, J=7.2, 16.7 Hz), 1.68 (t, 2H, J=7.2 Hz), 1.52-1.45 (m, 1H), 0.86 (d, 3H, J=7.0 Hz), 0.83 (d, 3H, J=6.6 Hz). Anal. Calculated for C27H29N5O3.HCO2H.0.5 EtOAc: C, 64.15; H, 6.28; N, 12.47. Found: C, 64.21, H, 6.40; N, 12.60.
Reaction SMILES: [O:1]=[S:2]1(=[O:31])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:30])[N:14]([N:23]=[C:24]3[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25]3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:31]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:30])[N:14]([NH:23][CH:24]3[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25]3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1
Reactant: CC1CCC(=Nn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3ccccc32)C1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1CCC(Nn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3ccccc32)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 236A (0.068 g, 0.16 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.010 mL, 0.28 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.100 mL, 0.20 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of approximately 2-4, diluted with water, and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with dichloromethane to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03 (m, 3 H) 1.35 (m, 1 H) 1.78 (m, 4 H) 2.56 (m, J=5.52 Hz, 2 H) 3.69 (m, 1 H) 5.78 (m, 1 H) 7.05 (m, 1 H) 7.27 (m, 2 H) 7.52 (m, 2 H) 7.69 (m, 2 H) 8.06 (dd, J=7.72, 1.47 Hz, 1 H) 16.28 (s, 1 H). MS (ESI−) m/z 437 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([Br:12])=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.CN.[CH3:16][N:17](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>[NH2:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([Br:12])=[CH:7][C:3]=1[C:4]([NH:17][CH3:16])=[O:5]
Reactant: Nc1cc(F)c(Br)cc1C(=O)O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(Br)c(F)cc1N

Procedure:
A solution of 2-amino-5-bromo-4-fluorobenzoic acid (2.00 g, 8.55 mmol), methylamine hydrochloride (0.692 g, 10.2 mmol), TBTU (2.74 g, 8.55 mmol), and DIPEA (4.46 mL, 25.6 mmol) in DCM (15.0 mL) was stirred at rt for 30 minutes. The reaction was quenched with sat. aq. NaHCO3 (10 mL) and extracted with DCM (15 mL). The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to a yellow oil. The crude material was purified on a Teledyne ISCO Combiflash® Rf system using DCM/MeOH (100:0→95:5) as eluent to afford the title compound as 2.54 g of a white solid. 1H NMR (CDCl3, 400 MHz): δ 7.48 (d, J=7.3 Hz, 1H), 6.44 (d, J=10.4 Hz, 1H), 6.11 (br. s., 1H), 5.66 (br. s., 2H), 2.96 (d, J=4.8 Hz, 3H). MS (ESI): m/z 248.91 [M+H]+. UPLC: tR=3.26 min (ZQ3: polar—5 min).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[CH:38]1([C:41](Cl)=[O:42])[CH2:40][CH2:39]1>O1CCCC1>[CH:38]1([C:41]([N:19]2[CH2:20][CH2:21][C:15]3[N:14]=[C:13]([C:11]4[S:12][C:8]5[C:7]([N:23]6[CH2:24][CH2:25][O:26][CH2:27][CH2:28]6)=[CH:6][CH:5]=[C:4]([O:3][CH3:2])[C:9]=5[N:10]=4)[NH:22][C:16]=3[CH2:17][CH2:18]2)=[O:42])[CH2:40][CH2:39]1
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCNCC4)nc12
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCN(C(=O)C3CC3)CC4)nc12
Yield: 93 %

Procedure:
To a suspension of 0.04 g 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepine hydrochloride in 3.4 ml tetrahydrofurane were added at 0–4° C. 0.07 ml N-ethyldiisopropylamine and 0.012 g cyclopropanecarbonyl chloride. The mixture was refluxed for 17 hours, silicagel was added and the solvent was distilled off. The residue was transferred to a column prefilled with silicagel and was chromatographed with dichloromethane/methanol 96:4 to yield 0.04 g (90%) cyclopropyl-[2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepin-6-yl]-methanone as yellow solid; MS (ISP): m/e=454 (M+H+).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[BH4-].[Na+]>C(O)C.O>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][OH:6]
Reactant: CSc1ccccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CSc1ccccc1CO
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1.00 g (6.57 mmol) of 2-methylsulfanylbenzaldehyde in 10 mL of ethanol at 0° C. was added 250 mg of NaBH4. The reaction was stirred at 0° C. for 10 min, then diluted with 50 mL of water. The aqueous suspension was extracted with diethyl ether (3×15 mL), then the combined ether layers were back extracted with brine (1×10 mL), dried over MgSO4, filtered, and concentrated in vacuo to 1.01 g (100%) of the titled compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]3[C:19]([CH3:22])=[N:20][N:21]=[C:11]3[CH:10](NNC(NN)=O)[N:9]=2)=[CH:4][CH:3]=1.Cl.[O:30]1[CH2:35]COCC1.N(OCCC(C)C)=O.[CH2:44]([NH2:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CN(C)C=O.C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:44]([NH:51][C:35]([CH:10]1[N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]12)=[O:30])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: Cc1nnc2n1-c1ccccc1C(c1ccc(Cl)cc1)=NC2NNC(=O)NN
Reactant: C1COCCO1
Reactant: NCc1ccccc1
Agent: CC(C)CCON=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nnc2n1-c1ccccc1C(c1ccc(Cl)cc1)=NC2C(=O)NCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of (±)-[6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]carbohydrazide (109.7 mg) in dimethylformamide (1 ml) was cooled to -40° C. and 4N dioxane hydrochloride (0.23 ml) was added thereto. The temperature of the mixture was raised to 0° C. The reaction mixture was cooled again to -40° C. and isopentyl nitrite (40 μl) was added thereto. The mixture was stirred at -30° C. for 1 hour. The temperature of the mixture was again cooled to -70° C. Triethylamine (0.125 ml) was added to the mixture and 10 minutes later, benzyl amine (77 μl) was added thereto. Then, the temperature of the mixture was raised to 0° C. and the mixture was stirred for 3 hours. The mixture was stirred at room temperature for 10 hours. Dimethylformamide was distilled away under reduced pressure and the residue obtained was dissolved in chloroform and washed with 0.3N hydrochloric acid, an aqueous solution of sodium bicarbonate and water in order and dried over anhydrous sodium sulfate. Chloroform was distilled away under reduced pressure and ethyl acetate was added to the residue to give 95.1 mg of (±)-N-benzyl-[6-(4-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]- benzodiazepin-4-yl]carboxamide as colorless needle crystals, mp. 265°-267° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]3[CH2:19][CH2:20][CH2:21]/[C:22](=[CH:23]\[C:24]4[CH:29]=[CH:28][C:27]([N:30]5[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]5)=[C:26]([O:36][CH3:37])[CH:25]=4)/[C:17]3=[N:16][C:15]=2[C:38](OC)=[O:39])=[CH:10][CH:9]=1.C(OCC)(=O)C.O>C1COCC1>[F:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:18]3[CH2:19][CH2:20][CH2:21]/[C:22](=[CH:23]\[C:24]4[CH:29]=[CH:28][C:27]([N:30]5[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]5)=[C:26]([O:36][CH3:37])[CH:25]=4)/[C:17]3=[N:16][C:15]=2[CH2:38][OH:39])=[CH:12][CH:13]=1
Reactant: COC(=O)c1nc2n(c1-c1ccc(F)cc1)CCC/C2=C\c1ccc(-n2cnc(C)c2)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(/C=C2\CCCn3c2nc(CO)c3-c2ccc(F)cc2)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 30.9 %

Procedure:
LAH (7 mg) was added to a solution of methyl 3-(4-fluorophenyl)-8-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene}-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylate (86 mg) in THF (3 mL), and the reaction solution was stirred at 0° C. for one hour. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate->ethyl acetate:methanol=5:1) to obtain 25 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH3:5])[O-:3].[Al+3:6].[CH3:7][CH:8]([CH2:10][CH3:11])[O-:9].[CH3:12][CH:13]([CH2:15][CH3:16])[O-:14].[OH2:17].[N+]([O-])(O)=[O:19]>C(O)(CC)C>[CH3:1][CH:2]([CH2:4][CH3:5])[O-:3].[Al+3:6].[CH3:7][CH:8]([CH2:10][CH3:11])[O-:9].[CH3:12][CH:13]([CH2:15][CH3:16])[O-:14].[OH2:19].[OH2:17].[OH2:3].[OH2:3].[Al:6]
Reactant: O=[N+]([O-])O
Agent: CCC(C)[O-]
Agent: [Al+3]
Solvent: CCC(C)O
Solvent: O
Product: [Al]
Reaction time: 3 h

Procedure:
Aluminum sec-butoxide was prepared in accordance with the process described in U.S. Pat. No. 4,242,271. A 75% mixed solution of this aluminum sec-butoxide in sec-butyl alcohol was hydrolyzed at 85° C. with a mixed solution of sec-butyl alcohol containing 30% of water to obtain an alumina slurry. After the alumina slurry Was aged at 125° C. for 3 hours in an electromagnetically stirring autoclave, water was immediately added to the alumina slurry until a solids content was 20%, and the thus-treated alumina slurry was cooled. The pH of the alumina slurry was adjusted with a 3.8% aqueous solution of nitric acid to obtain Alumina Hydrate 6A. Alumina hydrate A obtained by drying colloidal sol of this alumina hydrate was determined by X-ray diffractometry and found to have a pseudoboehmite structure. At this time, the BET specific surface area was 175 m2/g, and the pore volume was 0.65 ml/g. Incidentally, the specific surface area and pore volume were determined by the following respective methods.