Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:37][CH2:38][O:39][CH3:40])=[C:13]([CH:36]=1)[C:14]([NH:16][C:17]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:26][C:18]=1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:15].Cl.Cl.[CH2:43]([N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)[CH2:44][CH3:45]>CC(C)=O>[CH3:40][O:39][CH2:38][O:37][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][N:49]2[CH2:50][CH2:51][N:46]([CH2:43][CH2:44][CH3:45])[CH2:47][CH2:48]2)=[CH:36][C:13]=1[C:14]([NH:16][C:17]1[CH:29]=[C:28]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:27]=[CH:26][C:18]=1[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[O:15]
Reactant: COCOc1ccc(CBr)cc1C(=O)Nc1cc(-c2ccccc2)ccc1C(=O)OC(C)(C)C
Reactant: CCCN1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCN1CCN(Cc2ccc(OCOC)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
Under ice-cooling, potassium carbonate (0.19 g) and tert-butyl 2-(5-(bromomethyl)-2-(methoxymethoxy)benzamido)-4-phenylbenzoate (0.12 g) were sequentially added to an acetone (1.8 mL) suspension of 1-propylpiperazine dihydrochloride (0.13 g), followed by stirring at room temperature for 5 hours and 30 minutes. The solvent was evaporated under reduced pressure, and a saturated aqueous solution of sodium bicarbonate and chloroform were added to the residue. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-90% chloroform/methanol] to obtain 0.088 g of tert-butyl 2-(2-(methoxymethoxy)-5-((4-propylpiperazin-1-yl)methyl)benzamido)-4-phenylbenzoate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=3)[C:11](=[O:32])[NH:10]2)=[CH:5][CH:4]=1)#[N:2].[Br:33]Br>C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][Br:33])[N:12]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:29])([F:31])[F:30])[CH:22]=3)[C:11](=[O:32])[NH:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)C1=C(C)N(c2ccc(F)c(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1=C(CBr)N(c2ccc(F)c(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 4-(4-cyanophenyl)-1-[4-fluoro-3-(trifluoromethyl)phenyl]-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (447 mg, 1.0 mmol) was dissolved in chloroform (10 ml) and bromine (176 mg, 1.10 mmol) was added at 0° C. The ice bath was removed and the mixture was stirred at room temperature for 0.5 h. The reaction mixture was then diluted with chloroform (20 ml) and washed successively with 10% strength aqueous sodium thiosulphate solution (10 ml) and concentrated aqueous sodium chloride solution (10 ml). The organic phase was separated off, dried over sodium sulphate, filtered and concentrated on a rotary evaporator. This gave 570 mg (quant.) of the target compound which was reacted further without further purification.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([OH:23])=O)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:39][C@H:40]([C:42]([NH:44][C@H:45]([C:49]([OH:51])=[O:50])[C@@H:46]([CH3:48])[OH:47])=[O:43])[CH3:41]>>[C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([NH:39][C@H:40]([C:42]([NH:44][C@H:45]([C:49]([OH:51])=[O:50])[C@@H:46]([CH3:48])[OH:47])=[O:43])[CH3:41])=[O:23])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C[C@H](N)C(=O)N[C@H](C(=O)O)[C@@H](C)O
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)O)[C@@H](C)O
Yield: 82.9 %

Procedure:
Starting from 3-hexadecanoyloxyoctadecanoic acid (150 mg) prepared by the method described in Preparation 2(3) and N-L-alanyl-L-threonine (303 mg), N-[N-(3-hexadecanoyloxyoctadecanoyl)-L-alanyl]-L-threonine (164 mg) was obtained as powder according to similar manner to that of Example 12.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]([C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][C:16]([N+:23]([O-])=O)=[CH:15][C:14]=2[N+:26]([O-])=O)[C:8](=[O:12])[O:9][CH2:10][CH3:11])=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([C:13]2[C:18]([C:19]([F:22])([F:20])[F:21])=[CH:17][C:16]([NH2:23])=[CH:15][C:14]=2[NH2:26])[C:8](=[O:12])[O:9][CH2:10][CH3:11])=[CH:29][CH:30]=1
Reactant: CCOC(=O)N(Cc1ccc(Cl)cc1)c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)N(Cc1ccc(Cl)cc1)c1c(N)cc(N)cc1C(F)(F)F
Reaction time: 7 h
Yield: 97.4 %

Procedure:
Ethyl 4-chlorobenzyl[2,4-dinitro-6-(trifluoromethyl)phenyl]carbamate (294.7 mg) was dissolved in ethyl acetate (20 ml), and to the solution was added 10% Pd—C (267.7 mg). The reaction mixture was stirred under hydrogen atmosphere for 7 hours. The catalyst was filtered, and washed with ethyl acetate. The filtrate was concentrated in vacuo to give the title compound (248.7 mg).
Reaction SMILES: C(OC([NH:8][CH:9]([CH:20]1[CH2:22][CH2:21]1)[C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1)=O)(C)(C)C.[ClH:23].O1CCOCC1>CO>[ClH:23].[NH2:8][CH:9]([CH:20]1[CH2:22][CH2:21]1)[C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(C(NC(=O)OC(C)(C)C)C2CC2)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C(N)C2CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 4-{[(tert-butoxycarbonyl)amino](cyclopropyl)methyl}benzoate (793 mg), methanol (5 mL), and 4 M hydrogen chloride/dioxane (5 mL) were mixed, followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and then to the residue was added ethyl acetate. The precipitated solid was collected by filtration and dried under reduced pressure to obtain methyl 4-[amino(cyclopropyl)methyl]benzoate hydrochloride (561 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:13]([CH3:14])[CH:12]=[CH:11][C:5]2=[N:6][C:7]=1[C@@H:8]([NH2:10])[CH3:9].[NH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([OH:21])[CH2:16]1.CC([O-])(C)C.[K+]>O1CCOCC1>[NH2:10][C@H:8]([C:7]1[N:6]=[C:5]2[CH:11]=[CH:12][N:13]([CH3:14])[C:4]2=[CH:3][C:2]=1[N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([OH:21])[CH2:16]1)[CH3:9]
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1Br
Reactant: OC1CCCNC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@H](N)c1nc2ccn(C)c2cc1N1CCCC(O)C1
Temperature: 150 °C
Yield: 273.4 %

Procedure:
A mixture of (S)-1-(6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethan-1-amine (508 mg, 2.00 mmol), piperidin-3-ol (1.01 g, 10.0 mmol) and potassium 2-methylpropan-2-olate (1.56 g, 14.0 mmol) in dioxane (15 mL) was heated to 150° C. for 2 hours in a microwave reactor. The solvent was evaporated in vacuo to give the crude product (1.5 g) as a yellow oil which was used in the next step without further purification. ESI-MS m/z [M+H]+ calc'd for C15H22N4O, 275. found 275.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1.[CH3:19][N:20]([CH3:40])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30](C2C=CC=CC=2)=[C:29]([CH:37]=O)[NH:28][C:27]=1[CH3:39])=[O:25]>>[CH3:19][N:20]([CH3:40])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[CH2:30][C:29]([CH:37]=[C:13]2[C:12]3[C:16](=[CH:17][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[CH:10][CH:11]=3)[NH:15][C:14]2=[O:18])=[N:28][C:27]=1[CH3:39])=[O:25]
Reactant: COc1ccccc1-c1ccc2c(c1)NC(=O)C2
Reactant: Cc1[nH]c(C=O)c(-c2ccccc2)c1C(=O)NCCN(C)C
Product: COc1ccccc1-c1ccc2c(c1)NC(=O)C2=CC1=NC(C)=C(C(=O)NCCN(C)C)C1
Yield: 51.8 %

Procedure:
6-(2-Methoxyphenyl)-1,3-dihydroindol-2-one (53 mg, 0.22 mmol) was condensed with 5-formyl-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid (2-dimethylaminoethyl)amide (65 mg) to give 0.05 g (44%) of the title compound as an orange gum.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[C:14](=[O:23])[C:15]([CH3:22])=[C:16]([CH3:21])[C:17](=[O:20])[C:18]=2[CH3:19])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH2:28](O)[CH3:29]>>[C:1]1([CH:7]([C:13]2[C:14](=[O:23])[C:15]([CH3:22])=[C:16]([CH3:21])[C:17](=[O:20])[C:18]=2[CH3:19])[CH2:8][CH2:9][C:10]([O:12][CH2:28][CH3:29])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1=C(C)C(=O)C(C(CCC(=O)O)c2ccccc2)=C(C)C1=O
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CCC(C1=C(C)C(=O)C(C)=C(C)C1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
4-Phenyl-4-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-butanoic acid (1.2 g) was dissolved in ethanol (50 ml), and thionyl chloride (0.4 ml) was added to the solution, followed by stirring at room temperature for 4 hours. After the reaction solution was concentrated under reduced pressure, the resulting residue was dissolved in isopropyl ether, and the organic layer was washed with water, dried and concentrated under reduced pressure. The residue was chromatographed on a silica gel column, and the object compound was eluted with isopropyl ether to give ethyl 4-phenyl-4-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)butanoate (1.1 g, 84%). Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 1. By following the procedure of this example, the Compound No. 42 was prepared.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].C(N(CC)CC)C.Cl[C:13]1[C:22]([C:23]([C:25](=[CH:31]N(C)C)[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:24])=[CH:21][C:20]2[C:15](=[CH:16][C:17]([F:36])=[C:18]([F:35])[CH:19]=2)[N:14]=1>ClC(Cl)Cl>[CH2:29]([O:28][C:26]([C:25]1[C:23](=[O:24])[C:22]2[CH:21]=[C:20]3[CH:19]=[C:18]([F:35])[C:17]([F:36])=[CH:16][C:15]3=[N:14][C:13]=2[N:4]([O:2][CH3:3])[CH:31]=1)=[O:27])[CH3:30]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(F)cc2nc1Cl
Reactant: CON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(OC)c2nc3cc(F)c(F)cc3cc2c1=O
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 79.8 %

Procedure:
A suspension of methoxylamine hydrochloride (1.7 g) in trichloromethane (40 cc) is treated with triethylamine (2.13 g). After 15 minutes' stirring at a temperature in the region of 20° C., the solution obtained is treated with ethyl 2-(2-chloro-6,7-difluoro-3-quinolinecarbonyl)-3-(dimethylamino)acrylate (3.69 g) and stirred for 4 hours and a half at approximately 20° C. The reaction mixture is concentrated to dryness under reduced pressure (20 kPa) at a temperature in the region of 50° C. The residue is taken up with ethanol (70 cc) and triethylamine (3.6 g) and heated for 30 minutes to a temperature in the region of 75° C. After cooling to approximately 20° C., the precipitate obtained is drained and washed with ethanol (3×30 cc). 3-Ethoxycarbonyl-7,8-difluoro-1-methoxy-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (2.67 g) is obtained in the form of a pale yellow solid, m.p. 266°-268° C.).
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:34]2([CH3:35])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:36])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:24][CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])[CH3:22])[CH2:12][C@@H:11]([O:37][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[OH:8][C@@H:9]1[C@@:34]2([CH3:35])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:36])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:24][CH2:25][C:26]([OH:29])([CH3:27])[CH3:28])[CH3:22])[CH2:12][C@@H:11]([OH:37])[CH2:10]1
Reactant: C[C@@H](OCCC(C)(C)O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H](OCCC(C)(C)O)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.7 %

Procedure:
A solution of 1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-(3-hydroxy-3-methylbutyloxy)pregna-5,7,16-triene (50 mg, 0.0775 mmol) in tetrahydrofuran (1 ml) was combined with 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (0.5 ml) and stirred at room temperature for 12 hours, then with heating under reflux for 5 hours. The reaction solution was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and brine successively, and the organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by preparative thin layer chromatography (0.5 mm×2, dichloromethane:ethanol=20:1, developed twice) to give the title compound as a colorless oil (23.8 mg, 74%) and recovered raw materials (6 mg, 12%).
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:14])[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][NH:12][CH:13]=2)=[CH:5][CH:4]=1.[Br:15][C:16]1[N:17]=[C:18](Br)[C:19]2[N:20]([CH:22]=[CH:23][N:24]=2)[CH:21]=1.O>CN(C=O)C.C(OCC)C>[Br:15][C:16]1[N:17]=[C:18]([N:12]2[CH:13]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([CH3:14])=[CH:8][CH:7]=3)[N:10]=[CH:11]2)[C:19]2[N:20]([CH:22]=[CH:23][N:24]=2)[CH:21]=1
Reactant: Cc1ccc(-c2c[nH]cn2)cc1
Reactant: Brc1cn2ccnc2c(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2cn(-c3nc(Br)cn4ccnc34)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
Sodium hydride (NaH) (144 milligrams (mg) of a 60% dispersion in mineral oil) is added to a solution of 4-p-tolyl-1H-imidazole (571 mg) in N,N,-dimethylformamide (DMF) (10 ml) and the mixture is stirred at room temperature (rt) for 0.5 hr. A solution of 6,8-dibromoimidazo[1,2-a]pyrazine (3) (1.0 g) in DMF (10 ml) is added. The mixture is stirred at room temperature (rt) for 16 hr. Water (50 ml) is added and the mixture is extracted with ethyl acetate (3×70 ml); extracts are washed with water (2×50 ml) and brine (1×50 ml), dried over magnesium sulfate (MgSO4), and evaporated in vacuo to give a waxy solid. The solid is slurried with a little diethyl ether and filtered to give 6-Bromo-8-(4-p-tolyl-imidazol-1-yl)-imidazo[1,2-a]pyrazine (4) (1.08 g) as a light brown solid.
Reaction SMILES: Br.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[C:6](=[O:14])[N:5]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]1=[O:21].[CH2:22]([O:29][C:30]1[CH:39]=[C:38]2[C:33]([C:34](Cl)=[N:35][CH:36]=[N:37]2)=[CH:32][C:31]=1[O:41][CH3:42])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:30]1[CH:39]=[C:38]2[C:33]([C:34]([N:18]3[CH2:19][CH2:20][CH:15]([N:5]4[C:6](=[O:14])[C:7]5[C:12](=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=5)[N:3]([CH3:2])[C:4]4=[O:21])[CH2:16][CH2:17]3)=[N:35][CH:36]=[N:37]2)=[CH:32][C:31]=1[O:41][CH3:42])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: Cc1ccc2c(c1)c(=O)n(C1CCNCC1)c(=O)n2C
Agent: Br
Product: COc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)ncnc2cc1OCc1ccccc1
Yield: 42 %

Procedure:
The procedure similar to that described in Example 57 was repeated, except that 369.0 mg (1.05 mmol) of 1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)quinazoline hydrobromide (Compound v) obtained in Example 41 was used and 7-benzyloxy-4-chloro-6-methoxyquinazoline was used in place of 4-chloro-6,7-dimethoxyquinazoline. As a result, 233.8 mg (yield: 42%) of Compound 87 was obtained as white crystals.
Reaction SMILES: NC1C=CC(C2C=NN(CCCO)C=2)=CC=1C(N(CC)CC)=O.[NH2:24][C:25]1[C:26]([C:40]([NH:42][CH3:43])=[O:41])=[N:27][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:30]=1.Br[C:45]1[C:46]([C:54]#[N:55])=[N:47][N:48]([CH2:50][CH2:51][CH2:52][OH:53])[CH:49]=1>>[NH2:24][C:25]1[C:26]([C:40]([NH:42][CH3:43])=[O:41])=[N:27][C:28]([C:45]2[C:46]([C:54]#[N:55])=[N:47][N:48]([CH2:50][CH2:51][CH2:52][OH:53])[CH:49]=2)=[CH:29][CH:30]=1
Reactant: N#Cc1nn(CCCO)cc1Br
Reactant: CNC(=O)c1nc(B2OC(C)(C)C(C)(C)O2)ccc1N
Agent: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Product: CNC(=O)c1nc(-c2cn(CCCO)nc2C#N)ccc1N
Yield: 23 %

Procedure:
Prepared analogously to Compound 3C using 3-amino-N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (Compound 48D, 657 mg, 2.37 mmol) and 4-bromo-1-(3-hydroxypropyl)-1H-pyrazole-3-carbonitrile (Compound 52E, 600 mg, 2.61 mmol) to afford 164 mg of the title compound (23%). 1H NMR (400 MHz, CD3OD) δ 8.29 (s, 1H), 7.57 (d, J=8.6 Hz, 1H), 7.21 (d, J=8.6 Hz, 1H), 4.35 (t, J=6.8 Hz, 2H), 3.57 (t, J=6.1 Hz, 2H), 2.94 (s, 3H), 2.11 (t, J=6.1 Hz, 2H). MS (ESI): m/z=301.24 [M+H]+. UPLC: tR=0.79 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [O:1]=[S:2]1(=[O:13])[CH:6]([CH3:7])[C:5]2[C:8]([Cl:12])=[CH:9][CH:10]=[CH:11][C:4]=2[NH:3]1.[N+:14]([O-])([O-:16])=[O:15].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[O:13]=[S:2]1(=[O:1])[CH:6]([CH3:7])[C:5]2[C:8]([Cl:12])=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[C:4]=2[NH:3]1
Reactant: O=[N+]([O-])[O-]
Reactant: CC1c2c(Cl)cccc2NS1(=O)=O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CC1c2c(Cl)ccc([N+](=O)[O-])c2NS1(=O)=O
Reaction time: 24 h
Yield: 20.7 %

Procedure:
1,3-dihydro-2,2-dioxo-4-chloro-3-methyl-2,1-benzisothiazole (200 mg, 0.92 mmol) was dissolved in methylene chloride (30 ml) followed by the addition of sodium nitrate (86 mg, 1.01 mmol). The addition of sulfuric acid (0.18 ml/3M) is then made, followed by addition of a catalytic amount of sodium nitrite. The mixture is allowed to stir. After about 24 hours, the reaction mixture is diluted with methylene chloride and extracted with water. The organic layer is dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (50% Ethyl acetate/Hexane) gave the desired product (50 mg, 21%). EI-MS m/z 263.5 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].CC(C[AlH]CC(C)C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][NH:13][CH2:12][CH2:11][NH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(-c2cnccn2)cc1Cl
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: Clc1ccc(C2CNCCN2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a solution of 2-(3,4-dichlorophenyl)pyrazine (10 g, 44.43 mmol) in dry THF (150 ml) was added slowly a solution of DIBAL-H (1 M in THF, 444.3 ml) through a dropping funnel at 10° C. under N2. The color of solution turned into red wine at the end of addition. The solution was gradually warmed up to room temperature overnight. After completion (checked by TLC) the reaction was quenched slowly by the addition of saturated Na2SO4 solution until no more H2 evolved. White precipitate was formed after stirring for 1.0 h. The precipitate was filtered off, rinsed with THF, dried over MgSO4 and evaporated to dryness. The crude material (10 g) was purified by flash chromatography on 300 g of flash grade silica gel in 7.5% NH3-MeOH/CH2Cl2 to give 4.11 g (17.77 mmol, 40%) of 2-(3,4-dichloro-phenyl)piperazine. m.p. 74-76° C.; FAB mass [M+1]+35Cl 231.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=1[NH:25][CH2:26][C:27]1[N:31]([CH3:32])[N:30]=[C:29]([CH3:33])[CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]4[CH2:16][CH2:15]4)=[O:13])[N:10]=3)[N:7]=2)=[CH:20][C:19]=1[NH:25][CH2:26][C:27]1[N:31]([CH3:32])[N:30]=[C:29]([CH3:33])[CH:28]=1
Reactant: Cc1cc(CNc2cc(O)ccc2Cl)n(C)n1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(CNc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2Cl)n(C)n1
Yield: 61.3 %

Procedure:
In the same manner as in Example 257 and using N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (210 mg, 0.65 mmol), 4-chloro-3-{[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]amino}phenol (240 mg, 0.97 mmol), potassium carbonate (220 mg, 1.6 mmol) and N,N-dimethylformamide (1.5 mL) as starting materials, the title compound (180 mg, 61%) was obtained as a brown solid.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:8]([N:10]2[CH:14]([C:15](O)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C[CH2:27][N:28](C(C)C)[CH:29](C)C.C(Cl)CCl.CNC>ClCCl.C1COCC1>[CH:1]1([CH2:6][C@@H:7]([C:8]([N:10]2[CH:14]([C:15]([N:28]([CH3:29])[CH3:27])=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)O
Agent: CNC
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CN(C)C(=O)C1CC=NN1C(=O)[C@@H](CC(=O)OC(C)(C)C)CC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of 1-{(2R)-2-(cyclopentylmethyl)-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoyl}-4,5-dihydro-1H-pyrazole-5-carboxylic acid (353 mg, 1.0 mmol), Hunig's base (0.35 ml, 2.0 mmol), EDC (231 mg, 1.2 mmol) and aza-HOBt (136 mg, 1.0 mmol) in dichloromethane (DCM) (10 ml) was added N-methylmethanamine (1.0 ml, 2.0 mmol), which was in THF. The reaction mixture was stirred at room temperature overnight. The mixture was then washed with water (5 mL), NaHCO3 solution (5 mL×3), and concentrated to provide the crude product which was purified by Combiflash automated silica gel chromatography (0-50% EtOAc in hex) to afford 1,1-dimethylethyl (3R)-3-(cyclopentyl methyl)-4-{5-[(dimethylamino)carbonyl]-4,5-dihydro-1H-pyrazol-1-yl}-4-oxobutanoate (315 mg, 0.83 mmol, 83% yield) as a yellow solid. MS: 380 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[NH:11][C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C.CC#N>[CH2:21]([N:11]1[C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[C:7]=2[CH:13]=[C:12]1[CH3:14])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc2c(ccc3nnc(C)n32)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1cc2c(ccc3nnc(C)n32)n1Cc1ccccc1
Reaction time: 2 h
Yield: 80.4 %

Procedure:
A solution of 1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (10. mg, 0.054 mmol, from Step 5) in DMF (1.5 mL) was treated with K2CO3 (22 mg, 0.16 mmol) and a solution of benzyl bromide (6.4 μL, 0.054 mmol, Aldrich) in DMF (0.10 mL). After stirring for 2 hours, the mixture was diluted with MeCN, filtered and purified via preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) to afford product (12 mg, 81%).