Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6](=[O:18])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)[CH3:2].[H-].[Na+].[N+:22]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1)([O-:24])=[O:23].Cl>C1COCC1>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([CH2:29][C:28]1[CH:31]=[CH:32][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=1)[C:6](=[O:18])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=1)[CH3:2]
Reactant: CCOC(=O)CC(=O)CCc1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)CCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 5-(4-nitro-phenyl)-3-oxo-pentanoic acid ethyl ester prepared in Example FF (14.2 g, 54 mmol) in dry THF (150 mL) was added NaH (2.43 g of a 60% dispersion in oil, 57.5 mmol), and the mixture was stirred at room temperature for 45 minutes. 4-Nitrobenzyl bromide (13.9 g, 64.3 mmol) was added all at once, and the resulting suspension was stirred overnight at room temperature. Dilute HCl (2N, 100 mL) was added. The solution was extracted with EtOAc; the extracts were combined, washed with brine, and dried (MgSO4). Concentration gave a residue which was chromatographed on silica gel, eluting with 5:1 hexane:EtOAc to 1:1 hexane:EtOAc, to yield the title compound. 1H NMR (CDCl3) δ 1.11 (t, 3 H), 2.66 (m, 1 H), 2.95 (m, 3 H), 3.21 (m, 2 H), 3.75 (t, 1 H), 4.07 (m, 2 H), 7.23 (m, 4 H), 8.05 (d, 4 H).
Reaction SMILES: [OH-].[K+].[C:3]1(=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>>[CH:3]1([CH:3]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C1CCCCC1
Agent: [K+]
Agent: [OH-]
Product: C1CCC(C2CCCCC2)CC1
Reaction time: 0.5 h

Procedure:
140 g KOH (solid) are added to 2,000 g (20.41 mol) cyclohexanone. The mixture is heated under reflux with stirring. After 0.5 h, the reaction is terminated. The mixture is analyzed by GC analysis.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)[C:7]([CH:19]=[CH:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:25])[CH3:26])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1cccc(C)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1cccc(C)c1

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(3-methylphenyl)-5-(pent-1-enyl)pyridine (Example 139) by the procedure described in Example 126. 1H NMR (300 MHz, CDCl3): δ 0.77 (t, J=7.0 Hz, 3 H), 1.0-1.40 (m, 19 H), 2.25 (m, 2 H), 2.39 (s, 3 H), 3.23 (m, 1 H), 3.44 (m, 1 H), 4.34 (s, 2 H), 6.97 (m, 2 H), 7.18-7.34 (m, 2 H). FAB-MS: calculated for C24H35NO 354; found 354 (M+H, 100 %). Rf=0.34 (10% ethyl acetate/n-hexane). mp 88-90° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([Cl:17])[CH:8]=2)=[N:5][N:6]=1.[CH2:18]([C:20]1[C:25](/[CH:26]=[CH:27]/[O:28][CH3:29])=[CH:24][CH:23]=[CH:22][C:21]=1B1OC(C)(C)C(C)(C)O1)[CH3:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:9]1[CH:8]=[C:7]([C:4]2[S:3][C:2]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25](/[CH:26]=[CH:27]/[O:28][CH3:29])[C:20]=3[CH2:18][CH3:19])=[N:6][N:5]=2)[CH:12]=[CH:11][C:10]=1[O:13][CH:14]([CH3:16])[CH3:15]
Reactant: CCc1c(/C=C/OC)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)Oc1ccc(-c2nnc(Br)s2)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(/C=C/OC)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 120 °C
Yield: 77.8 %

Procedure:
To a suspension of 2-bromo-5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazole (D10) (300 mg), 2-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (259 mg) and tripotassium phosphate (477 mg) in N,N-dimethylformamide (DMF) (8 mL) and water (2 mL) under nitrogen was added Pd(Ph3P)4 (104 mg). The reaction vessel was sealed and heated under microwave at 120° C. for 10 min. The reaction mixture was extracted with EA for 3 times, the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, the dried solution was concentrated, and purified by column chromatography to afford 2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-5-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,3,4-thiadiazole (D14) (290 mg) as a yellow oil. MS (ES): C22H23ClN2O2S requires 414. found 415.2 (M+H+).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[Br-].[Li+].[CH2:18]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1.O.CCCCCC>[CH2:18]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C:31]([OH:34])([C:15]2[C:10]([F:9])=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:30][CH2:29]1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Fc1ccccn1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(O)(c2cccnc2F)CC1
Temperature: -50 °C

Procedure:
To a solution of lithium diisopropylamide (0.31 mol) in 300 mL of anhydrous tetrahydrofuran:hexane at -78° C. was added a solution of 2-fluoropyridine (24.6 mL) in 40 mL of anhydrous tetrahydrofuran. The reaction mixture was allowed to warm to -50° C., cooled back to -74° C. and treated dropwise with a solution of lithium bromide (55.5 g) and 1-benzyloxycarbonyl-4-oxopiperidine (55.5 g) in 300 mL of anhydrous tetrahydrofuran so that the temperature of the reaction mixture remained below -70° C. After the addition was complete, the reaction mixture was allowed to warm to -30° C. and then treated with water. The organic layer was separated and the aqueous layer was extracted with two portions of ether. Combined organic layers were dried and evaporated to afford the crude product. This material was purified by column chromatography to afford the pure product.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]#[C:4][CH2:5][CH2:6][CH:7]1[CH2:9][O:8]1.C(O)(=O)C.[Li+].[Br-:17]>C1COCC1>[Br:17][CH2:9][CH:7]([OH:8])[CH2:6][CH2:5][C:4]#[C:3][Si:2]([CH3:11])([CH3:10])[CH3:1]
Reactant: C[Si](C)(C)C#CCCC1CO1
Reactant: [Br-]
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CCCC(O)CBr
Reaction time: 8 h
Yield: 37.2 %

Procedure:
To a stirred solution of trimethyl(4-(oxiran-2-yl)but-1-ynyl)silane (4.5 g, 27 mmol) in THF (90 mL) containing acetic acid (4.81 g, 80.21 mmol), was added at 0° C. ahydrous LiBr (3.71 g, 42.78 mmol). The reaction mixture was left stiffing overnight at room temperature. The reaction was quenched with saturated NaCl and extracted with Et2O. The organic phase was washed once with a solution of 1M K2CO3 saturated with NaCl, brine, dried over MgSO4, filtered and concentrated. The crude residue was purified over silicagel chromatography (prepacked 70 g silicagel column, from Cyclohxane 100% to DCM 100% as eluent) to afford 2.5 g of 1-bromo-6-(trimethylsilyl)hex-5-yn-2-ol (Yield: 38%) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][N:13]([C:15]2[N:20]=[C:19]([CH3:21])[CH:18]=[C:17]([NH:22][C:23]3[NH:27][N:26]=[CH:25][CH:24]=3)[N:16]=2)[CH2:12][C@@H:11]([C:28]([O:30]C)=[O:29])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[NH4+].[Cl-]>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][N:13]([C:15]2[N:20]=[C:19]([CH3:21])[CH:18]=[C:17]([NH:22][C:23]3[NH:27][N:26]=[CH:25][CH:24]=3)[N:16]=2)[CH2:12][C@@H:11]([C:28]([OH:30])=[O:29])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H]1C[C@@H](NC(=O)OC(C)(C)C)CN(c2nc(C)cc(Nc3ccn[nH]3)n2)C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Nc2ccn[nH]2)nc(N2C[C@@H](NC(=O)OC(C)(C)C)C[C@H](C(=O)O)C2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The crude carbamate was dissolved into MeOH (4 ml). 2 M aqueous solution of NaOH was added at room temperature. And the mixture was stirred at room temperature for 4 hours. After the addition of NH4Cl for neutrallization, the resulting reaction mixture was concentrated in vacuo. The residue was suspended into the mixed solvent of CHCl3/MeOH. The insoluble material was filtered off and the filtrate was concentrated again. The residue was purified with silica gel PTLC (eluent: CHCl3/MeOH=6/1) to give trans-5-[(tert-butoxycarbonyl)amino]-1-[4-methyl-6-(1H-pyrazol-5-ylamino)pyrimidin-2-yl]piperidine-3-carboxylic acid (10.9 mg) as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[CH2:11][N:10]([CH2:23][C:24]3[CH:25]=[N:26][C:27](Cl)=[CH:28][CH:29]=3)[C:9]2=[O:31])=[CH:4][CH:3]=1.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[CH:14]=3)[CH2:11][N:10]([CH2:23][C:24]3[CH:25]=[N:26][C:27]([N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:28][CH:29]=3)[C:9]2=[O:31])=[CH:6][CH:7]=1
Reactant: C1CCNCC1
Reactant: O=C1N(Cc2ccc(Cl)nc2)C[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: O=C1N(Cc2ccc(N3CCCCC3)nc2)C[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Cl)cc1
Temperature: 130 °C

Procedure:
A mixture of (S)-3-(4-chlorophenyl)-1-((6-chloropyridin-3-yl)methyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one (34 mg, 0.073 mmol), piperidine (0.5 mL) and pyridine (2 mL) are heated for 2 days at 130° C. The residue is purified by preparatory LC/MS to provide the title compound; 1H NMR (CD3OD, 400 MHz) δ 7.89 (dd, J=9.6, 6.4 Hz, 1H), 7.75 (d, J=1.6 Hz, 1H), 7.50-7.41 (m, 4H), 7.32-7.27 (m, 3H), 7.15 (d, J=9.2 Hz, 2H), 5.45 (dd, J=9.2, 6.4 Hz, 1H), 4.34 (s, 2H), 3.88 (t, J=9.2 Hz, 1H), 3.60-3.58 (m, 4H), 3.16 (dd, J=9.0, 6.2 Hz, 1H), 1.72-1.61 (m, 6H); HPLC-MS calculated for C27H26ClF3N4O (M+H+) 515.1, found 515.1.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:10](=[O:31])[CH:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])[CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1.Cl.O>C(OCC)C.[Cl-].[Zn+2].[Cl-]>[F:3][C:4]1[CH:5]=[C:6]([CH:10]([OH:31])[CH:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])[CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(=O)c1cccc(F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of zinc chloride (5.60 g, 41.1 mmol) in diethyl ether (140 ml) was added sodium borohydride (3.11 g, 82.2 mmol), and the mixture was stirred at room temperature for 30 min. Insoluble material was filtered off. To the filtrate was added a solution of ethyl 3-(3-fluorophenyl)-3-oxo-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate (8.56 g, 20.6 mmol) in diethyl ether (50 ml) at 0° C., and the mixture was stirred for 30 min. 1N Hydrochloric acid was added to the reaction solution to stop the reaction. Then, water (100 ml) was added and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried (anhydrous magnesium sulfate), and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the objective substance (7.04 g, 82%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](OC)=[O:9])[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[CH2:13])[N:3]=1.CN(C=O)C.[BH4-].[Na+].C(O)(=O)C>CO.O>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[CH2:13])[N:3]=1
Reactant: C=C(OCC)c1cc(C(=O)OC)nc(Cl)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C=C(OCC)c1cc(CO)nc(Cl)n1
Yield: 58.2 %

Procedure:
Methyl 2-chloro-6-(1-ethoxyvinyl)pyrimidine-4-carboxylate (3.5 g, 14.4 mmol) was dissolved in MeOH (35 mL), DMF (24.50 mL) and water (3.5 mL) by careful heating. The mixture was cooled on an ice-bath and sodium borohydride (1.47 g, 38.9 mmol) was added in small portions (about 50 mg every 5 min) keeping the temperature below 5° C. After 3.5 h acetic acid (3.96 mL, 69.23 mmol) was added. MeOH was evaporated and water was added. The mixture was extracted with diisopropyl ether (3×50 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The product was purified by column chromatography on silica eluting with a gradient of EtOAc in heptane to give the title compound as a solid 1.8 g (58%).
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41](O)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.Cl.Cl.[NH:50]1[C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=2[N:52]=[C:51]1[CH2:59][NH2:60]>>[NH:50]1[C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=2[N:52]=[C:51]1[CH2:59][NH:60][C:41]([C:39]1[S:40][C:36]([N:33]2[CH2:34][CH2:35][N:31]([CH2:30][C:29]3[CH:28]=[CH:27][C:26]([F:25])=[CH:47][CH:46]=3)[C:32]2=[O:45])=[CH:37][C:38]=1[CH3:44])=[O:42]
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1nc2ccccc2[nH]1
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Agent: Cl
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1nc2ccccc2[nH]1
Yield: 80 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (1H-benzo[d]imidazol-2-yl)methanamine dihydrochloride, the title compound was obtained as a colorless solid in 80% yield: mp 265-267° C.; 1H NMR (300 MHz, DMSO-d6) δ 12.19 (br s, 1H), 8.23 (t, J=5.5 Hz, 1H), 7.54-7.46 (m, 2H), 7.38-7.31 (m, 2H), 7.24-7.10 (m, 4H), 6.25 (s, 1H), 4.60 (d, J=5.5 Hz, 2H), 4.39 (s, 2H), 3.87-3.78 (m, 2H), 3.48-3.39 (m, 2H), 2.42 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 163.1, 159.9, 155.5, 152.5, 142.9, 139.2, 132.9 (d, JC-F=3.0 Hz), 129.9 (d, JC-F=8.2 Hz), 121.3, 120.0, 115.3 (d, JC-F=21.2 Hz), 112.1, 46.3, 42.5, 41.3, 37.7, 15.8; MS (ES+) m/z 464.4 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[C:9]([Br:12])[C:5]2=[N:6][S:7][N:8]=[C:4]2[C:3]=1[Br:13].[CH3:14][C:15](=O)[C:16](=O)[CH3:17].O>C(O)(=O)C>[Br:13][C:3]1[C:4]2[C:5](=[N:6][S:7][N:8]=2)[C:9]([Br:12])=[C:10]2[C:2]=1[N:1]=[C:16]([CH3:17])[C:15]([CH3:14])=[N:11]2
Reactant: Nc1c(N)c(Br)c2nsnc2c1Br
Reactant: CC(=O)C(C)=O
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc2c(Br)c3nsnc3c(Br)c2nc1C
Temperature: 25 °C
Reaction time: 19 h

Procedure:
5,6-Diamino-4,7-dibromobenzo[c][1,2,5]thiadiazole (0.257 g, 7.93×10−4 mol) was dissolved in acetic acid (30 ml). 2,3-Butanedione (0.30 ml, 3.4×10−3 mol) was added, and the reaction mixture was stirred for 19 h at room temperature under N2. Water (50 ml) was added, and the resulting precipitate was filtered, dissolved in CH2Cl2, washed with water, and dried over Na2SO4. After the solvent was evaporated, the residue was chromatographed on silica gel with CHCl3. Yield=0.256 g (86% based on 0.257 g of 5,6-diamino-4,7-dibromobenzo[c][1,2,5]thiadiazole). 1H NMR (360 MHz, CDCl3): δ 2.88 (s, 6H, —CH3). Chemical Ionization MS m/z: 371.8675 (M+) (calcd 371.868).
Reaction SMILES: CC([N:5](C(O)=O)[NH:6][C:7](=[O:23])[C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=1)(C)C.Cl.[OH-].[Na+]>O1CCCC1.O>[CH3:22][C:19]([C:10]1[CH:9]=[C:8]([CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]=1[OH:18])[C:7]([NH:6][NH2:5])=[O:23])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1cc(C(=O)NN(C(=O)O)C(C)(C)C)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(=O)NN)cc(C(C)(C)C)c1O
Reaction time: 0.33 h
Yield: 65.3 %

Procedure:
1,1-Dimethylethyl 2-[3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoyl]hydrazine carboxylic acid (4.0 g, 0.011 mole) in tetrahydrofuran (100 ml) is treated with a mixture of water (12 ml) and concentrated hydrochloric acid (30 ml). The resulting mixture is heated on a steam-bath. After 20 minutes the mixture is stripped of volatiles under reduced pressure. The residue is dissolved in water (100 ml) and treated with 1M NaOH until the solution is slightly basic. The product is extracted into ether (600 ml) and the organic layer is washed with saturated aqueous NaCl and dried over MgSO4. Filtration and concentration provides a solid which is recrystallized from isopropyl ether/hexane to yield 1.9 g (2.9 g theor., 66%) of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoic acid, hydrazide, mp 187°-188° C.
Reaction SMILES: C([BH3-])#N.[Na+].[CH2:5]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][N:17]([C:19]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[O:20])[CH2:16][CH:15]([C:27]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:28])[CH2:14]2)=[CH:9][CH:8]=1)[CH3:6].C(O[C:39]1(O[Si](C)(C)C)[CH2:41][CH2:40]1)C.C(O)(=O)C>O1CCCC1.CO>[CH:39]1([N:24]2[CH2:25][CH2:26][N:21]([C:19]([N:17]3[CH2:18][CH:13]([C:10]4[CH:11]=[CH:12][C:7]([CH2:5][CH3:6])=[CH:8][CH:9]=4)[CH2:14][CH:15]([C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:28])[CH2:16]3)=[O:20])[CH2:22][CH2:23]2)[CH2:41][CH2:40]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: CCc1ccc(C2CC(C(=O)Nc3ccccc3)CN(C(=O)N3CCNCC3)C2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc(C2CC(C(=O)Nc3ccccc3)CN(C(=O)N3CCN(C4CC4)CC3)C2)cc1

Procedure:
At RT, 898 μl of a 1-molar solution of sodium cyanoborohydride in tetrahydrofuran were added to a solution of 94 mg (0.20 mmol) of 5-(4-ethylphenyl)-N-phenyl-1-(piperazin-1-ylcarbonyl)piperidine-3-carboxamide, 241 μl (1.20 mmol, 6 eq.) of [(1-ethoxycyclopropyl)oxy](trimethyl)silane, 35 μl (0.62 mmol, 3.1 eq.) of acetic acid and 115 mg of molecular sieves (4 {acute over (Å)}) in 1 ml of methanol. The reaction mixture was stirred under reflux for 5 h and then filtered and adjusted to pH 8 using a 0.2-molar sodium hydroxide solution. After addition of water/dichloromethane and phase separation, the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried (sodium sulphate), filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 60 mg (65% of theory)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:11])[CH2:9][CH3:10].[C:12]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:17])[CH2:13][C:14]([O-])=[O:15].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>O.C1COCC1>[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:14](=[O:15])[CH2:13][C:12]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])(=[O:11])[CH2:9][CH3:10]
Reactant: CCC(=O)c1ccccc1N
Reactant: O=C([O-])CC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CCC(=O)c1ccccc1NC(=O)CC(=O)OCc1ccccc1
Yield: 17.9 %

Procedure:
To a mixture of 1-(2-aminophenyl)propan-1-one (CAS1196-28-7) (4.6 g), monobenzyl malonate (7.2 g), and THF (46 mL) were added EDC.HCl (7.1 g) and HOBt.H2O (7.1 g), and the mixture was stirred at room temperature for 14 h and then heated to reflux for 8 h. The solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate and then washed with saturated aqueous sodium hydrogencarbonate and saturated brine. The organic layer was dried with anhydrous sodium sulfate, the desiccant was removed by filtration, then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=9:1) to obtain benzyl N-(2-propionylphenyl)malonamate (1.8 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[N:2]=1.Cl[CH:9]([CH:15]=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11]>CCO>[N:7]1[CH:15]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:2]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:1]2
Reactant: Nc1cccnn1
Reactant: CCOC(=O)C(Cl)C=O
Solvent: CCO
Product: CCOC(=O)c1cnc2cccnn12
Temperature: 25 °C
Yield: 40.8 %

Procedure:
A mixture of pyridazin-3-amine (9.51 g, 0.1 mol) and 2-ethyl 2-chloro-3-oxopropanoate (22.5 g, 0.15 mol) in EtOH (20 mL) was stirred at reflux overnight. The mixture was allowed to cool to RT and concentrated in vacuo to remove EtOH. The residue was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo. The residue was slurried in isopropyl ether (50 mL) with stirring for 30 min, collected by filtration and dried in vacuo to afford ethyl imidazo[1,2-b]pyridazine-3-carboxylate (7.8 g, 40.8% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([NH:24][O:25]C4CCCCO4)=[O:23])=[CH:16][CH:15]=3)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.CO.Cl.CC#N>CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([NH:24][OH:25])=[O:23])=[CH:16][CH:15]=3)[CH2:9]2)=[O:7])=[CH:32][CH:33]=1
Reactant: O=C(/C=C/c1ccc(N[C@@H]2CCN(C(=O)c3ccc(Cl)cc3)C2)cc1)NOC1CCCCO1
Agent: Cl
Solvent: CC#N
Solvent: CO
Product: O=C(/C=C/c1ccc(N[C@@H]2CCN(C(=O)c3ccc(Cl)cc3)C2)cc1)NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 187.7 %

Procedure:
To a solution of (2E)-3-(4-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}phenyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (76 mg) in MeOH (1.3 mL) was added hydrogen chloride methanol reagent 10 (0.32 mL, Tokyo Kasei), and the mixture was stirred at ambient temperature for 1 hour. To the reaction mixture was added CH3CN and the solvent was removed in vacuo. Obtained colorless solid was triturated with CH3CN to give (2E)-3-(4-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}phenyl)-N-hydroxyacrylamide hydrochloride (64.1 mg) as colorless powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]#[C:21][CH2:22][CH2:23][CH3:24].C[Si](C#C)(C)C>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:20]#[C:21][CH2:22][CH2:23][CH3:24])[CH:15]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCCC
Reactant: Brc1ccc2cc(OCc3ccccc3)ccc2c1
Agent: C#C[Si](C)(C)C
Product: CCCC#Cc1ccc2cc(OCc3ccccc3)ccc2c1

Procedure:
The reaction was conducted in the same manner as in the step (i) of the Example 31, except for using 2-(benzyloxy)-6-bromonaphthalene synthesized in the step (i) and 1-n-pentyne instead of 1-bromo-4-n-propylbenzene and trimethylsilylacetylene, respectively. The resultant was recrystallized from ethanol to give 2-(benzyloxy)-6-(2-n-propylethynyl)naphthalene.