Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[OH:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:34]4[CH2:35][CH2:36][CH:31]([OH:30])[CH2:32][CH2:33]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: OC1CCNCC1
Reactant: ClCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: OC1CCN(CCOc2n[nH]c3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)CC1
Yield: 25 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and 4-hydroxypiperidine to give the title compound in 25% yield; NMR Spectrum: 1.34-1.37 (m, 2H), 1.66-1.69 (m, 2H), 2.15 (t, 2H), 2.76-2.80 (m, 4H), 4.40 (t, 2H), 5.28 (s, 2H), 7.24 (d, 1H), 7.37 (t, 1H), 7.54-7.58 (m, 2H), 7.87-7.91 (m, 2H), 8.29 (s, 1H), 8.47 (br s, 1H), 8.59 (d, 1H); Mass Spectrum: 496 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:14][CH3:15])[C:12]=1[OH:13])[CH:6]=[CH:7][CH:8]=O.[C:16]([CH2:18][C:19]([N-:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:20])#[N:17]>>[C:25]1([CH2:24][CH2:23][CH2:22][NH:21][C:19](/[C:18](=[CH:8]/[CH:7]=[CH:6]/[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:12]([OH:13])=[C:11]([O:14][CH3:15])[CH:10]=2)/[C:16]#[N:17])=[O:20])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: N#CCC(=O)[N-]CCCc1ccccc1
Reactant: COc1cc(C=CC=O)cc(OC)c1O
Product: COc1cc(/C=C/C=C(\C#N)C(=O)NCCCc2ccccc2)cc(OC)c1O
Yield: 90.2 %

Procedure:
The compound was prepared as described in Example 3 by adding 3,5-dimethoxy-4-hydroxycinnamaldehyde (0.10 g, 0.48 mmol) to N-(cyanoacetyl)phenylpropylamide (Example 19, 0.097 g, 0.48 mmol). After refluxing for 3 h the residue was purified by silica gel chromatography (CHCl3-hexane, 1:1) to give a brown solid (0.17 g, 90% yield). The product gave the following analytical data:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C@@H:7]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([NH:16][C@@H:17]([CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:18][NH:19]C(=O)OCC[Si](C)(C)C)=[O:15])[CH2:9]1.[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43].C(Cl)Cl>>[F:45][C:44]([F:47])([F:46])[C:42]([OH:48])=[O:43].[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C@@H:7]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([NH:16][C@@H:17]([CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:18][NH2:19])=[O:15])[CH2:9]1
Reactant: COCCCO[C@@H](c1ccccc1)[C@@H]1CCCN(C(=O)N[C@H](CNC(=O)OCC[Si](C)(C)C)CC2CCCCC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCCO[C@@H](c1ccccc1)[C@@H]1CCCN(C(=O)N[C@H](CN)CC2CCCCC2)C1
Reaction time: 0.5 h

Procedure:
2-(Trimethylsilyl)ethyl (S)-2-((R)-3-((R)-(3-methoxypropoxy)(phenyl)methyl)piperidine-1-carboxamido)-3-cyclohexylpropylcarbamate (85.3 mg, 0.14 mmol) was dissolved in 6 mL 1:1 TFA/CH2Cl2 (6 mL) and stirred for 30 min. LC-MS showed the reaction was complete. After concentration, (3R)-3-((R)-(3-methoxypropoxy)(phenyl)methyl)-N-((S)-1-amino-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide trifluoroacetic acid salt was isolated by prep HPLC. LC-MS (3 min) tR=1.56 min, m/z 446 (M+1). 1H NMR (CD3OD) δ 7.37-7.25 (m, 5H), 4.30 (d, 1H), 4.03 (m, 1H), 4.97-4.90 (m, 2H), 3.50-3.39 (m, 2H), 3.27 (s, 3H), 3.00 (dd, 1H), 2.85-2.75 (m, 3H), 1.81-0.82 (m, 22H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:22][OH:23].C(=O)([O-])[O-].[Na+].[Na+].Cl>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[N:22][OH:23])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(F)cc2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCC(=NO)c1ccc(-c2ccc(F)cc2)cc1
Yield: 92.6 %

Procedure:
A stirred mixture of 4-(4′-fluoro-biphenyl-4-yl)-4-oxo-butyric acid (2.72 g, 0.0100 mol), hydroxylamine hydrochloride (0.848 g, 0.0122 mol) and sodium carbonate (1.304 g, 0.0123 mol) in absolute ethanol (60 mL) was refluxed for 22 hours and allowed to cool. The solids were filtered, washed with additional ethanol, and allowed to air dry overnight. The solids were dissolve din methanol-water, and the solution acidified with 1.0 M hydrochloric acid (10 mL, 0.010 mol HCl). The mixture was concentrated to approximately 30 mL on a rotary evaporator, and the resulting precipitate filtered and dried in vacuo to give 2.66 g of 4-(4′-fluoro-biphenyl-4-yl)-4-hydroxyimino-butyric acid as a pale yellow solid; mp 152-153° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[NH:8][C:7](=S)[CH2:6][CH2:5]2.[C:14]([NH:17][NH2:18])(=O)[CH3:15]>C(O)CCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[N:8]1[C:14]([CH3:15])=[N:17][N:18]=[C:7]1[CH2:6][CH2:5]2
Reactant: Fc1cc(Br)cc2c1NC(=S)CC2
Reactant: CC(=O)NN
Solvent: CCCCO
Product: Cc1nnc2n1-c1c(F)cc(Br)cc1CC2
Temperature: 120 °C

Procedure:
To a stirred solution of 6-bromo-8-fluoro-3,4-dihydroquinoline-2(1H)-thione (109-4; 3.0 g, 0.011 mol) in n-butanol (25 mL) was added acetic hydrazide (4.81 g, 0.065 mol) and then followed by the addition of molecular sieves. Reaction mass was heated to 120° C. for 16 h. The reaction mixture was concentrated and directly purified by silica gel column chromatography to obtain title compound. MS (M+1): 284.2.
Reaction SMILES: [CH2:1]([CH:3]1[O:7]C=[N:5][CH:4]1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].C(N(CC)CC)C.Cl>O>[NH2:5][CH:4]([CH:3]([OH:7])[CH2:1][CH3:2])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1N=COC1CC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C(N)C(O)CC
Yield: 96.9 %

Procedure:
Ethyl 5-ethyl-2-oxazoline-4-carboxylate (10.3 g), water (1.62 ml) and triethylamine (0.086 ml) were stirred at 100° C. for 3 hours. To this mixture was added 5N HCl (26 ml) and the mixture diluted to 100 ml with water, washed twice with methylene chloride and brought to pH 10 with 50% sodium hydroxide solution. The solution was extracted with methylene chloride (6 × 30 ml), dried and evaporated to yield the racemic title compound (e11) (9.4 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[OH:11])[C:7](=[O:12])[CH2:6][CH2:5]2.[N-:13]=[N+]=[N-].[Na+].O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[OH:11])[C:7](=[O:12])[NH:13][CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(F)c(O)cc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C1NCCc2cc(F)c(O)cc21
Reaction time: 3 h

Procedure:
To a solution of 5-fluoro-6-hydroxyindan-1-one ((90), 10.5 g, 63.3 mmol) in chloroform (600 ml) was added NaN3 (12.3 g, 190 mmol), followed by dropwise addition of methanasulfonic acid (33 ml, 506 mmol). Resulting mixture was stirred for 3 hr. The reaction mixture was poured into cold water and extracted with chloroform (3×). Organic extracts were combined and washed with H2O and sat. NaCl, then dried over Na2SO4. Concentration in vacuo gave a mixture of required product and reversed lactam. Purification of crude product on silica eluting with 30-60% EtOAc/Hexane offered the title compound as a off-white solid (5.3 g, 46%). MS (ES) m/z 180.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][N:12](C(OC)=O)[CH2:11][CH2:10]1.O.NN.[OH-].[K+]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[N:9]1[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]1
Reactant: COC(=O)N1CCN(c2ccncc2OC)CC1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cnccc1N1CCNCC1
Yield: 46.2 %

Procedure:
A solution of methyl 4-(3-methoxy-4-pyridinyl)-1-piperazinecarboxylate (1.2 g, 4.7 mmol) in 50 mL of EtOH containing 1 mL of 85% hydrazine hydrate and potassium hydroxide (12 g, 210 mol) was heated to reflux for 12 h. The reaction mixture was cooled, concentrated in vacuo and the residue dissolved in EtOAc. The organic extracts were dried (brine, MgSO4), filtered and concentrated in vacuo. Silica gel chromatography (3:1:0.01 CH2Cl2 -MeOH-Et3N) of the residue gave the desired compound (0.42 g, 46%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O.[C:8]([NH:15][C@H:16]([C:21](O)=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>>[C:8]([NH:15][C@H:16]([C:21]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:22])[CH2:17][CH:18]([CH3:19])[CH3:20])([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C1COCCN1
Solvent: O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCOCC1

Procedure:
In substantially the same manner as Working Example 2, morpholine (1.76 ml) was condensed with Boc-L-leucine monohydrate (5.00 g) to give Boc-L-leucylmorpholine (5.76 g) as a colorless oily product (yield 95%). A portion (2.00 g) of this product was taken, and the Boc group was deprotected by using TFA. The resultant compound was treated in substantially the same manner as Working Example 8 to afford L-leucylmorpholine hydrochloride (1.52 g) as a white powdery product (yield 96%). A portion (807 mg) of this product was condensed, in substantially the same manner as Working Example 8, with (2S,3S)-ethyl hydrogen N-Z-aziridine-2,3-dicarboxylate (Compound 1, 100 g) to afford the above-titled compound (Compound 17; 1.06 g) as a white powdery product (yield 65%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20]Cl)=[CH:16][CH:15]=2)=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:22][NH:23][CH3:24]>>[CH3:1][O:2][C:3]([C:5]1([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:23]([CH3:24])[CH3:22])=[CH:16][CH:15]=2)=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: CNC
Reactant: COC(=O)C1(NC(=O)c2ccc(CCl)cc2)CCCCC1
Product: COC(=O)C1(NC(=O)c2ccc(CN(C)C)cc2)CCCCC1
Reaction time: 8 h
Yield: 50 %

Procedure:
30 ml of 40% aqueous dimethylamine solution was added to 4.5 g (14.5 mmol) of 1-[[[4-(chloromethyl)phenyl]carbonyl]amino]cyclohexanecarboxylic acid methyl ester, and the mixture was heated under reflux for 3 hours. The reaction mixture was distilled off under reduced pressure, a saturated aqueous sodium bicarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, diisopropyl ether was added to the residue, and the mixture was stirred overnight. The precipitated solid was collected by filtration to obtain 2.3 g (50%) of the title compound.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[C:10]([N:16]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][C@H:18]([OH:20])[CH3:19])=[N:11][C:12]([Br:15])=[CH:13][CH:14]=1.N1C=CC=CC=1>ClCCl>[CH2:21]([N:16]([CH2:17][C@H:18]([OH:20])[CH3:19])[C:10]1[C:9]([NH:8][C:1](=[O:3])[CH3:2])=[CH:14][CH:13]=[C:12]([Br:15])[N:11]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: C[C@@H](O)CN(Cc1ccccc1)c1nc(Br)ccc1N
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(Br)nc1N(Cc1ccccc1)C[C@@H](C)O
Temperature: 40 °C
Yield: 55.7 %

Procedure:
Acetic anhydride (0.623 mL, 6.60 mmol) was added to a solution of crude (R)-1-((3-amino-6-bromopyridin-2-yl)(benzyl)amino)propan-2-ol (2.22 g, 6.60 mmol) and pyridine (1.60 mL, 19.8 mmol) in dichloromethane (60 mL). The reaction mixture was then heated to 40° C. for 39 h. The reaction mixture was concentrated under reduced pressure. The crude residue was dissolved in toluene (ca. 100 mL), which was then concentrated under reduced pressure in order to remove residual pyridine. The crude product was purified by column chromatography on silica gel (eluting with 2:1 dichloromethane-ethyl acetate followed by 3:2 dichloromethane-ethyl acetate) to afford (R)-N-(2-(benzyl(2-hydroxypropyl)amino)-6-bromopyridin-3-yl)acetamide (1.39 g, 56% yield). MS (ESI, pos. ion) m/z 378, 380 [M+1]+.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][CH3:17])[S:15][C:9]=2[NH:8][C:7]1=[O:18].O[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[C:34]([C:40]#[N:41])=[CH:35][CH:36]=[C:37]([F:39])[CH:38]=2)=[CH:29][CH:28]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C(OCC)(=O)C.O1CCCC1>[CH2:16]([C:14]1[S:15][C:9]2[N:8]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[C:34]([C:40]#[N:41])=[CH:35][CH:36]=[C:37]([F:39])[CH:38]=4)=[CH:29][CH:28]=3)[C:7](=[O:18])[NH:6][C:11](=[O:12])[C:10]=2[CH:13]=1)[CH3:17]
Reactant: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)[nH]c2s1
Reactant: N#Cc1ccc(F)cc1-c1ccc(CO)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4cc(F)ccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.5 %

Procedure:
A mixture of 3-(2,4-dimethoxybenzyl)-6-ethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.5 g), 4′-(hydroxymethyl)-5-fluorobiphenyl-2-carbonitrile (1.3 g), 1,1′-(azodicarbonyl)dipiperidine (1.6 g), tributylphosphine (1.3 mL) and tetrahydrofuran (16 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in trifluoroacetic acid (15 mL) and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was concentrated under reduced pressure. To the obtained residue was added ethyl acetate, and insoluble material was filtered off. The filtrate was concentrated and recrystallized from diethyl ether to give the title compound as a colorless solid (1.8 g, 100%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([O-])([O-:13])([O:10]CC)C>>[OH:7][C@H:1]1[CH2:6][CH:5]=[CH:4][C@H:3]1[CH2:2][C:8]([OH:13])=[O:10]
Reactant: Oc1ccccc1
Reactant: CCOC(C)([O-])[O-]
Product: O=C(O)C[C@@H]1C=CC[C@@H]1O

Procedure:
In the same manner as described in Example 1 but using 0.5 part of phenol in place of the hydroquinone, 7 parts of unreacted ethyl orthoacetate was recovered and then 4.2 parts of the desired product, a lactone of cis-2-hydroxy-cyclopent-4-ene-1-acetic acid was obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)=[N:5][S:6][C:7]=1[CH:8]=[CH2:9].[OH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:21]([CH3:32])[C:20]=1[CH3:33]>>[CH:8]([C:7]1[S:6][N:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)[C:3]=1[CH2:2][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:21]([CH3:32])[C:20]=1[CH3:33])=[CH2:9]
Reactant: C=Cc1snc(-c2ccc(CC)cc2)c1CCl
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Product: C=Cc1snc(-c2ccc(CC)cc2)c1COc1ccc(CCC(=O)OCC)c(C)c1C

Procedure:
The title compound was prepared according to the procedure described in Example 122 following Step 5 by coupling of 4-(chloromethyl)-3-(4-ethylphenyl)-5-vinylisothiazole with ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate to afford the desired product as a yellow oil. Mass spectrum (ESI, m/z): Calcd. for C27H31NO3S, 450.2 (M−H). found 450.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][C:26]=1[C:34]([F:37])([F:36])[F:35].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:1][C:2]2[CH:23]=[CH:22][CH:21]=[C:4]([O:5][C:6]3[CH:7]=[CH:8][C:9]4[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]5[CH2:20][CH2:19]5)=[O:17])[N:14]=4)[N:11]=3)[CH:3]=2)=[O:30])=[CH:27][C:26]=1[C:34]([F:35])([F:36])[F:37]
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: O=C(O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
To a solution of N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (100 mg, 0.32 mmol) in N,N-dimethylformamide (6.0 mL) were added 4-chloro-3-(trifluoromethyl)benzoic acid (73 mg, 0.32 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (65 mg, 0.34 mmol) and 1-hydroxybenzotriazole (46 mg, 0.34 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→80/20) and precipitated from ethyl acetate/diisopropyl ether to give the title compound (130 mg, 77%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](B(O)O)=[CH:8][C:7]=2[CH:14]=1.Cl[C:16]1[C:25]([N:26]([CH:28]([CH3:30])[CH3:29])[CH3:27])=[N:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:31]([O:33][CH2:34]C)=[O:32])[CH:22]=2)[N:17]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[CH:28]([N:26]([CH3:27])[C:25]1[C:16]([C:9]2[O:10][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:14][C:7]=3[CH:8]=2)=[N:17][CH:18]2[CH:23]([N:24]=1)[CH:22]=[C:21]([C:31]([O:33][CH3:34])=[O:32])[CH:20]=[CH:19]2)([CH3:30])[CH3:29]
Reactant: COc1ccc2oc(B(O)O)cc2c1
Reactant: CCOC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
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: C1COCCO1
Solvent: O
Product: COC(=O)C1=CC2N=C(N(C)C(C)C)C(c3cc4cc(OC)ccc4o3)=NC2C=C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
To a solution of 5-methoxybenzofuran-2-ylboronic acid (275.0 mg, 1.43 mmol) in dioxane (5.0 mL) was added ethyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (140.0 mg, 0.48 mmol), K3PO4 (302.0 mg, 1.43 mmol) and Pd(PPh3)4 (27.5 mg, 0.02 mmol) and water (3 drops) with stirring for 1 h at 90° C. in an oil bath maintained with an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 1% ethyl acetate in petroleum ether to afford methyl 3-(isopropyl(methyl)amino)-2-(5-methoxybenzofuran-2-yl)-4a,8a-dihydroquinoxaline-6-carboxylate as a light yellow solid (150.0 mg, 73%).
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([NH:13][CH2:14][C:15](O)=[O:16])=[O:12])[CH2:10][CH:5]2[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:3]1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[N:30]1([C:15](=[O:16])[CH2:14][NH:13][C:11]([N:9]2[CH2:8][CH2:7][N:6]3[C:2](=[O:1])[O:3][C:4]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:5]3[CH2:10]2)=[O:12])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: C1COCCN1
Reactant: O=C(O)CNC(=O)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CNC(=O)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1)N1CCOCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 51 %

Procedure:
N-[(Tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-7(1H)-yl)carbonyl]glycine (0.15 g, 0.38 mmol) was dissolved in N,N-dimethylformamide (3 mL). Morpholine (0.14 g, 1.2 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.15 g, 0.76 mmol) and 1-hydroxybenzotriazole (0.11 g, 0.77 mmol) were added thereto, and the mixture was stirred at room temperature for 20 hours. To the reaction solution was added ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, an aqueous saturated sodium hydrogen carbonate solution and water and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:methanol=95:5) and powder was formed from hexane to obtain the title compound (90 mg, yield 51%).
Reaction SMILES: [OH:1][CH:2]([C:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6])[C:3]#[N:4].Cl.C[OH:21]>>[OH:1][CH:2]([C:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:6])[C:3]([NH2:4])=[O:21]
Reactant: CC(c1ccccc1)(c1ccccc1)C(O)C#N
Reactant: CO
Agent: Cl
Product: CC(c1ccccc1)(c1ccccc1)C(O)C(N)=O
Temperature: 5 °C
Reaction time: 16 h

Procedure:
10.0 g (4.22 [sic] mmol) of 2-hydroxy-3,3-diphenylbutyronitrile were dissolved in 500 ml of methanol (abs.) and, at 5-10° C., HCl was passed in for 3 hours. The mixture was then stirred at 5° C. for 3 hours and at room temperature for 16 hours. Then 200 ml of 6 molar HCl were added and the mixture was evaporated to dryness under reduced pressure. The crude product was recrystallized from an ethyl acetate/heptane mixture. 2.5 g (23%) of 2-hydroxy-3,3-dihenylbutyramide were obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[C:5]([CH3:12])([CH3:11])[CH2:4][CH2:3]1.[C:14](Cl)(=[O:16])[CH3:15].[Sn](Cl)(Cl)(Cl)Cl.Cl>C1C=CC=CC=1.O>[C:14]([C:8]1[S:7][C:6]2[C:5]([CH3:12])([CH3:11])[CH2:4][CH2:3][C:2]([CH3:13])([CH3:1])[C:10]=2[CH:9]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)Cl
Reactant: CC1(C)CCC(C)(C)c2sccc21
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: O
Product: CC(=O)c1cc2c(s1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 98 %

Procedure:
18.2 g of 4,5,6,7-tetrahydro-4,4,7,7-tetramethylbenzo-[b]thiophene and 7.4 g of acetyl chloride are dissolved in 200 ml of benzene and the solution is cooled to 0° C. At this temperature there are slowly added dropwise thereto 24.4 g of tin tetrachloride. After stirring at room temperature for 2.5 hours, the mixture is again cooled to 0° C. and a mixture of 9.3 ml of concentrated hydrochloric acid and 36.4 ml of water is added dropwise thereto. The mixture is extracted with ether, the organic phase is washed once with water, dried, evaporated and distilled in a high vacuum. There are obtained 21.7 g of 2-acetyl-4,5,6,7-tetrahydro-4,4,7,7-tetramethylbenzo[b]thiophene as a colorless liquid, b.p. 108°-115° C./0.05 mm, which can be crystallized from hexane, m.p. 53°-55° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Cl:21])[C:18]=1[O:19][CH3:20])[C:5]([N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9][CH2:8]1)=[O:6].ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Cl:21])[C:18]=1[O:19][CH3:20])[C:5]([N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9](=[O:30])[CH2:8]1)=[O:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1c(Cl)cc(C(=O)N2CSc3ccccc32)cc1Cl
Solvent: ClC(Cl)Cl
Product: COc1c(Cl)cc(C(=O)N2CS(=O)c3ccccc32)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64.2 %

Procedure:
3-(3,5-dichloro-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole (500 mg) was dissolved in chloroform (10 mL), and 70% metachloroperbenzoic acid (320 mg) was added to the solution, and the mixture was stirred at 0° C. for 10 minutes. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain the title compound (336 mg) as a colorless crystal.