Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:18]=[CH:17][N:16]=[C:15](C=O)[CH:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[BH4-].[Na+].C[OH:24]>>[OH:24][C:15]1[CH:14]=[C:13]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)[N:18]=[CH:17][N:16]=1
Reactant: COc1cc(-c2cc(C=O)ncn2)cc(OC)c1OC
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: COc1cc(-c2cc(O)ncn2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-(3,4,5-Trimethoxyphenyl)pyrimidine-4-carboaldehyde (364 mg) was dissolved in methanol (50 mL), and to the solution sodium borohydride (25 mg) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (chloroform:methanol=50:1) to obtain the title compound.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][C:12]1[CH:13]=[C:14](/[CH:24]=[CH:25]/[C:26]([NH:28][NH2:29])=[O:27])[CH:15]=[CH:16][C:17]=1[N:18]1[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]1.[C:30]([CH2:38][CH2:39][CH2:40][C:41](O)=[O:42])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:10][O:11][C:12]1[CH:13]=[C:14](/[CH:24]=[CH:25]/[C:26]([NH:28][NH:29][C:41](=[O:42])[CH2:40][CH2:39][CH2:38][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:27])[CH:15]=[CH:16][C:17]=1[N:18]1[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]1
Reactant: COc1cc(/C=C/C(=O)NN)ccc1-n1cnc(C)c1
Reactant: O=C(O)CCCC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(/C=C/C(=O)NNC(=O)CCCC(=O)c2ccccc2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.2 %

Procedure:
IPEA (2.5 mL) was added to a suspension of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid hydrazide (500 mg) in methylene chloride (12 mL) at room temperature, and the reaction solution was stirred at room temperature for 10 minutes. 4-benzoylbutyric acid (334 mg) and BOPCl (442 mg) were added to the reaction solution at room temperature, and the reaction solution was stirred at room temperature for four hours. A saturated sodium bicarbonate solution was added to the reaction solution, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure to obtain 5-oxo-5-phenylpentanoic acid N′-{(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloyl}hydrazide (692 mg). Imidazole (494 mg), carbon tetrabromide (2.36 g) and triphenylphosphine (559 mg) were added to a suspension of 5-oxo-5-phenylpentanoic acid N′-{(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloyl}hydrazide (634 mg) in methylene chloride (15 mL) at room temperature, and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system, then ethyl acetate-methanol system) to obtain 515 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[C:9]1[N:27]=[C:12]2[C:13]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[CH:14][CH:15]=[CH:16][N:11]2[N:10]=1>>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][NH:17][C:13]1[C:12]2[N:11]([N:10]=[C:9]([NH:1][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[N:27]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cccnc1
Reactant: COc1ccccc1CNc1cccn2nc(Cl)nc12
Product: COc1ccccc1CNc1cccn2nc(Nc3cccnc3)nc12

Procedure:
N(8)-(2-Methoxy-benzyl)-N(2)-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from 3-aminopyridine (36.47 mg, 0.3875 mmol) and (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methoxy-benzyl)-amine (99.9 mg, 0.346 mmol) in a manner analogous to Example 2d. Product isolated as an off-white foam (19.21 mg, 16%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.68 (s, 1H), 8.88 (s, 1H), 8.21 (d, J=8.6 Hz, 1H), 8.09 (s, 1H), 7.99 (d, J=7.5 Hz, 1H), 7.33-7.20 (m, 3H), 7.03 (d, J=8.6 Hz, 1H), 6.87 (t, J=15.2, 8.1 Hz, 1H), 6.77 (t, J=13.5, 6.6 Hz, 1H), 6.31 (m, 2H), 4.47 (d, J=5.8 Hz, 2H), 3.87 (s, 3H). MS=347 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH:25]=O)[CH:7]=1)[CH3:2].[CH2:28]([NH2:30])[CH3:29]>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][C:16]=2[CH2:25][NH:30][CH2:28][CH3:29])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2C=O)c1
Reactant: CCN
Product: CCNCc1cc(C(F)(F)F)ccc1Oc1cc(CC(=O)OCC)ccc1OC

Procedure:
Prepared according to the procedure described in Example 3, Step 2, using the following starting materials: [3-(2-formyl-4-trifluoromethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and ethylamine (2M in THF).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:32]([F:35])([F:34])[F:33])[O:13][N:12]=[C:11]([C:14]3[CH:29]=[CH:28][C:17]([C:18]([NH:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[O:19])=[C:16]([NH:30][CH3:31])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[CH2:37]OCCl>ClCCl>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:32]([F:34])([F:33])[F:35])[O:13][N:12]=[C:11]([C:14]3[CH:15]=[C:16]4[C:17]([C:18](=[O:19])[N:20]([CH2:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=5)[CH2:31][N:30]4[CH3:37])=[CH:28][CH:29]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: ClCOCCl
Reactant: CNc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCc1ccccn1
Solvent: ClCCl
Product: CN1CN(Cc2ccccn2)C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc21
Reaction time: 15 h
Yield: 65.2 %

Procedure:
In a solution of 0.06 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylamino-N-(2-pyridylmethyl)benzoic acid amide (Compound of the present invention No. 5-332) synthesized similarly to Synthetic Example 18 in 5 ml of dichloromethane, 0.03 g of chloromethylether was added, and stirred at the same temperature for 15 hours After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (3:1) to obtain 0.04 g of the aimed product as colorless oily substance.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18]C(=O)C)=[CH:15][CH:16]=2)[CH:11]=[C:10]1[C:22]([O:24]CC)=[O:23]>CO.C1COCC1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[CH:11]=[C:10]1[C:22]([OH:24])=[O:23]
Reactant: CCOC(=O)c1cc2cc(OC(C)=O)ccc2n1Cc1ccc(Cl)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(Cn2c(C(=O)O)cc3cc(O)ccc32)ccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.3 %

Procedure:
Sodium hydroxide (2M, 1.9 ml) was added to a stirred solution of ethyl N-(3-methoxy-4-chlorobenzyl)-5-acetoxyindole-2-carboxylate (305 mg) in methanol (3 ml) and THF (3 ml). The reaction was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and then diluted with water (5 ml). The solution was acidified by the addition of aqueous hydrochloric acid (2M), extracted with ethyl acetate, dried and evaporated. The residue was purified by column chromatography eluting 20%-100% ethyl acetate to give the desired product as a solid (177 mg, 70%) NMR (CD3SOCD3): d 3.95 (s, 3H), 5.95 (s, 2H), 6.35 (d, 1H), 6.8 (dd, 1H), 6.9 (d, 1H), 7.0 (d, 1 μl), 7.1 (s, 1H), 7.25 (d, 1H), 7.3 (d, 1H), 9.0 (s, 1H); m/z 332 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:20])([CH3:19])[CH2:4][C@H:5]1[CH2:9][O:8]C(C)(C)[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].CC1C=CC(S(O)(=O)=O)=CC=1>CO>[OH:8][CH2:9][C@@H:5]([NH:6][C:12](=[O:13])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4][C:3]([O:2][CH3:1])([CH3:20])[CH3:19]
Reactant: COC(C)(C)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(C)(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Yield: 90.4 %

Procedure:
To a solution of (S)-tert-butyl 4-(2-methoxy-2-methylpropyl)-2,2-dimethyloxazolidine-3-carboxylate (1.2 g, 3.40 mmol) in MeOH (5 mL) at rt, there was added 4-methylbenzenesulfonic acid (0.65 g, 3.40 mmol). The resulting solution was stirred until no starting material remained (˜1 h). Solvent was removed under vacuum, and the residue was redissolved in acetone (3 mL) and H2O (1 mL). Excess K2CO3 was added to keep the solution basic, followed by (Boc)2O. The mixture was stirred for 20 min, acetone was removed under vacuum, and the aqueous solution was extracted with CH2Cl2 (4×5 mL). After concentration, the residue was purified by flash column chromatography to give (S)-tert-butyl 1-hydroxy-4-methoxy-4-methylpentan-2-ylcarbamate (0.76 g, 78%, 2 steps). 1H NMR (400 MHz, CDCl3): 5.38 (br, 1H), 3.78 (m, 1H), 3.66 (m, 1H), 3.56 (m, 1H), 3.20 (s, 3H), 1.66 (m, 2H), 1.62 (br, 1H), 1.44 (s, 9H), 1.20 (s, 6H); MS m/z 248 (M+H+).
Reaction SMILES: COC1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]([CH3:16])[N:10]=2)=[CH:5][C:4]=1C.Br.[C:19]([OH:22])(=O)[CH3:20]>>[CH3:16][N:11]1[C:12]([CH3:15])=[C:13]([CH3:14])[C:9]([C:6]2[C:7]([CH3:8])=[C:19]([OH:22])[CH:20]=[CH:4][CH:5]=2)=[N:10]1
Reactant: CC(=O)O
Reactant: COc1ccc(-c2nn(C)c(C)c2C)cc1C
Agent: Br
Product: Cc1c(O)cccc1-c1nn(C)c(C)c1C

Procedure:
A mixture of 3-(4-methoxy-3-methyl-phenyl)-1,4,5-trimethyl-1H-pyrazole (described in Reference Preparation example 65) 0.6 g, 47% hydrobromic acid 5 ml and acetic acid 5 ml was stirred with heating under reflux for thirteen hours. The solvent was distilled off and to the resulting residues was added ethyl acetate 30 ml, and the resulting mixture was stirred at room temperature for one hour. The precipitates were filtered and were washed with hexane, and were concentrated under reduced pressure to give (1,4,5-trimethyl-1H-pyrazol-3-yl)-2-methyl-phenol 0.5 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:17][CH2:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:4]=1.[CH3:32][O:33][C:34]1[C:35](=O)[C:36](=[O:40])[C:37]=1[O:38]C>CO>[CH3:32][O:33][C:34]1[C:37](=[O:38])[C:36](=[O:40])[C:35]=1[NH:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[NH:17][CH2:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:11]=1
Reactant: COc1c(OC)c(=O)c1=O
Reactant: COc1ccc(C(NCC(c2ccccc2)c2ccccc2)c2cccc(N)c2)cc1
Solvent: CO
Product: COc1ccc(C(NCC(c2ccccc2)c2ccccc2)c2cccc(Nc3c(OC)c(=O)c3=O)c2)cc1
Yield: 52.6 %

Procedure:
In a similar manner to that described in Example (1c), a solution of 3-[(4-methoxyphenyl)-(2,2-diphenylethylamino)methyl]phenylamine (2.02 g) [prepared as described in step (b) above] in methanol (40 ml) and 3,4-dimethoxy-3-cyclobutene-1,2-dione (731 mg) were reacted, to afford the title compound (1.35 g) as a white foamy solid.
Reaction SMILES: CO[C:3]([C:5]1[C:10]([NH:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].C[O-].[Na+]>CO>[OH:17][C:12]1[C:13]([C:14](=[O:16])[CH3:15])=[C:3]([OH:4])[C:5]2[C:10]([N:11]=1)=[N:9][CH:8]=[CH:7][N:6]=2
Reactant: COC(=O)c1nccnc1NC(=O)CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)c1c(O)nc2nccnc2c1O
Reaction time: 16 h
Yield: 77.8 %

Procedure:
3-(3-Oxo-butyrylamino)-pyrazine-2-carboxylic acid methyl ester (Example 6.1) (15 g) in methanol (80 ml) was added to a suspension of sodium methoxide (7.2 g) in methanol (80 ml). The suspension was heated to reflux for 2 hours and then stored for 16 hours at ambient temperature. The mixture was filtered and the filtrate was acidified to pH 1 by addition of concentrated hydrochloric acid (36% by weight in water) and then filtered again. The solid was washed with water and then diethyl ether to give 1-(6,8-dihydroxy-pyrido[2,3-b]pyrazin-7-yl)-ethanone (10.1 g). 1H-NMR (400 MHz, d6-DMSO): 2.70 (s, 3H), 8.60 (d, 1H), 8.71 (d, 1H), 12.2 (s, 1H), 16.25 (s, 1H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:21][C:20]1=[O:35].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(N(CC)CC)C>[CH2:28]([O:27][C:25]([N:22]1[CH2:23][CH2:24][N:19]([NH:18][C:15](=[O:17])[CH2:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)[C:20](=[O:35])[CH2:21]1)=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: NN1CCN(C(=O)OCc2ccccc2)CC1=O
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)NN2CCN(C(=O)OCc3ccccc3)CC2=O)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.9 %

Procedure:
A solution of 1-(tert-butoxycarbonyl)-4-piperidinylacetic acid (440 mg), 1-amino-4-benzyloxycarbonyl-2-piperazinone (541 mg), triethylamine (273 mg) and HOBt (333 mg) in DMF (30 ml) was combined with WSC (518 mg) and stirred at room temperature for 15 hours. The reaction mixture was concentrated to obtain a residue, which was partitioned between ethyl acetate and water, and the organic phase was washed with water, aqueous sodium bicarbonate, an aqueous solution of citric acid and brine, dried and concentrated to obtain N-(4-benzyloxycarbonyl-2-oxo-1-piperazinyl)-2-[1-(tert-butoxycarbonyl)-4-piperidinyl]acetamide (840 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]([C:5]1[N:6]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C:9]=12)=[O:4].[ClH:26]>O1CCOCC1>[ClH:26].[CH3:1][N:2]([CH3:25])[C:3]([C:5]1[N:6]=[C:7]([C:21]([F:24])([F:22])[F:23])[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C:9]=12)=[O:4]
Reactant: CN(C)C(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)C(=O)c1nc(C(F)(F)F)n2c1CNCC2
Reaction time: 12 h

Procedure:
Crude tert-butyl 1-(dimethylcarbamoyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-c]pyrazine-7-carboxylate 22a (362 mg, 1 mmol) was dissolved in 3 mL of a 2 M solution of hydrogen chloride in 1,4-dioxane. After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure to obtain crude N,N-dimethyl-3-(trifluoromethyl)-5,6,7,8-tetrahydro imidazo[1,5-a]pyrazine-1-carboxamide hydrochloride 22b (262 mg) as a light yellow solid. The product was used directly in the next reaction without purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[F:25])[CH:21]([CH3:26])[NH:20][CH2:19][CH2:18]2>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:20]3[CH2:19][CH2:18][C:17]4[C:22](=[CH:23][C:24]([F:25])=[C:15]([F:14])[CH:16]=4)[CH:21]3[CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2cc(F)c(F)cc21
Product: CC1c2cc(F)c(F)cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-difluoro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]([NH:26][S:27]([C:30]1[CH:31]=[CH:32][C:33]2[CH:37]=[CH:36][S:35][C:34]=2[CH:38]=1)(=[O:29])=[O:28])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OB(OC(C)C)OC(C)C)(C)C.C(=O)([O-])[O-].[Na+].[Na+].[Cl:58][C:59]1[N:64]=[C:63](Cl)[C:62]([CH3:66])=[CH:61][N:60]=1>C1COCC1.O>[CH:13]([NH:26][S:27]([C:30]1[CH:31]=[CH:32][C:33]2[CH:37]=[C:36]([C:61]3[C:62]([CH3:66])=[CH:63][N:64]=[C:59]([Cl:58])[N:60]=3)[S:35][C:34]=2[CH:38]=1)(=[O:29])=[O:28])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(=O)(NC(c1ccccc1)c1ccccc1)c1ccc2ccsc2c1
Reactant: Cc1cnc(Cl)nc1Cl
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: O=C([O-])[O-]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(Cl)nc1-c1cc2ccc(S(=O)(=O)NC(c3ccccc3)c3ccccc3)cc2s1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
To a solution of diisopropylamine (2.09 mL, 14.87 mmol) in dry THF (10 mL) is added a solution of n-butyllithium (1.6 M in hexane, 9.14 mL, 14.62 mmol) at −78° C. under a nitrogen atmosphere, the mixture is stirred for 30 minutes. A solution of benzo[b]thiophene-6-sulfonic acid benzhydrylamide (925 mg, 2.44 mmol) and triisopropylborate (2.87 mL, 12.43 mmol) in dry THF (10 mL) is added. The mixture is slowly warmed to 10° C. over 1 hour and stirred at room temperature for 30 minutes. A solution of sodium carbonate (2 M in water, 3.78 mL) is added followed by the addition of 2,4 dichloro5-methylpyrimidine (517 mg, 3.17 mmol) and (1,1′-bis(diphenylphosphino)ferrocene)palladium (II) chloride (99.6 mg, 0.122 mmol). The mixture is heated at 60° C. for 1.5 hours then cooled to room temperature. Water (40 mL) is added and the mixture is extracted with EtOAc (3×40 mL). The organic layers are dried (MgSO4) and concentrated. The residue is chromatographed on silica gel, eluting with hexanes/EtOAc 90:10 to 40:60, to give the title compound as a yellow solid (457 mg, 37% yield).
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([NH:10][NH:11][CH:12]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH2:13][CH2:14][CH2:15][C:16](OC)=[O:17])=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl>CO>[C:3]([O:7][C:8](=[O:9])[NH:10][N:11]1[C:16](=[O:17])[CH2:15][CH2:14][CH2:13][CH:12]1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: COC(=O)CCCC(NNC(=O)OC(C)(C)C)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NN1C(=O)CCCC1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.1 %

Procedure:
A 1 N sodium hydroxide solution (0.6 mL) was added to a solution of methyl 5-(N′-tert-butoxycarbonylhydrazino)-5-(4-fluorophenyl)pentanoate (81 mg) in methanol (1 mL), and the reaction solution was stirred at room temperature for two hours. 2 N aqueous hydrochloric acid (0.3 mL) was added to the reaction solution, and the reaction solution was concentrated under reduced pressure. HOBT (64 mg) and EDC (91 mg) were added to a solution of the residue in DMF (1 mL), and the reaction solution was stirred at room temperature for two hours. Ethyl acetate and saturated sodium bicarbonate 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: heptane:ethyl acetate=9:1->ethyl acetate) to obtain 50 mg of the title compound. The property values, of the compound are as follows.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)=[O:6].[NH:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:32][C:33](=[O:36])[CH2:34][CH3:35])[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1>>[O:6]=[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[CH2:4][CH2:3][CH2:2][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:32][C:33](=[O:36])[CH2:34][CH3:35])[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1
Reactant: O=C(CCCCl)c1ccc(Oc2ccccc2)cc1
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCC(=O)c3ccc(Oc4ccccc4)cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 4-chloro-1-(4-phenoxyphenyl)-1-butanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 471.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.[CH2:21]([O:28][C:29]1[C:34]([CH3:35])=[CH:33][C:32]([C:36]([C:38]2[CH:43]=[C:42](Cl)[N:41]=[CH:40][N:39]=2)=[O:37])=[CH:31][C:30]=1[CH3:45])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:21]([O:28][C:29]1[C:30]([CH3:45])=[CH:31][C:32]([C:36]([C:38]2[N:39]=[CH:40][N:41]=[C:42]([N:17]3[CH2:18][CH2:19][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:15][CH2:16]3)[CH:43]=2)=[O:37])=[CH:33][C:34]=1[CH3:35])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc(C)c1OCc1ccccc1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c(OCc5ccccc5)c(C)c4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
200 mg (0.730 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 240 mg (0.680 mmol) (4-benzyloxy-3,5-dimethyl-phenyl)-(6-chloro-pyrimidin-4-yl)-methanone and 0.400 mL (2.30 mmol) DIPEA were combined in 2.0 mL DMF and stirred for 3 h at RT. The mixture was added to ice water, the precipitate was suction filtered and dried.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[C:5]2[OH:13].Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[CH:17][CH:16]=[C:15]2[O:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=[C:7]([CH3:12])[CH:6]=1
Reactant: Cc1cc(O)c2cc(F)ccc2n1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc(C)nc4ccc(F)cc34)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h
Yield: 6.8 %

Procedure:
6-Fluoro-2-methyl-quinolin-4-ol (237 mg), 4-chloro-6,7-dimethoxyquinoline (100 mg), and 4-dimethylaminopyridine (164 mg) were suspended in o-dichlorobenzene (6 ml), and the suspension was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (11 mg, yield 7%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][Br:13]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cc(CBr)c(Cl)cc1Cl

Procedure:
This compound was prepared in a manner similar to Example 1 Step F using 2,4-dichloro-5-nitrotoluene (62.0 g, 0.3 mole), N-bromosuccinimide (160.2 g, 0.9 mole), benzoyl peroxide (2.0 g) and carbon tetrachloride (500 ml) to yield (2,4-dichloro-5-nitrophenyl)methyl bromide. The NMR spectrum was consistent with the proposed structure.