Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]=[CH:19][C:20]([N:22]([O:24][CH3:25])[CH3:23])=[O:21])[CH:16]=2)[CH:11]=[CH:10]1>C1COCC1>[CH3:25][O:24][N:22]([CH3:23])[C:20]([CH:19]1[CH2:2][CH:18]1[C:15]1[CH:16]=[C:17]2[C:12]([CH:11]=[CH:10][NH:9]2)=[CH:13][CH:14]=1)=[O:21]
Reactant: CON(C)C(=O)C=Cc1ccc2cc[nH]c2c1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CON(C)C(=O)C1CC1c1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.8 %

Procedure:
Trimethylsulfoxonium iodide (2.20 g, 10.00 mmol) was added to a suspension of sodium hydride (60% dispersion in oil, 0.40 g, 10.00 mmol) in anhydrous THF and stirred at room temperature for 1 h. 3-(1H-Indol-6-yl)-N-methoxy-N-methylacrylamide (0.90 g, 3.90 mmol) was dissolved in anhydrous THF and added dropwise to the cloudy white suspension. The mixture was stirred for 16 h at room temperature. The reaction was quenched with a solution of saturated ammonium chloride. Water was added and the solution was extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give 2-(1H-indol-6-yl)-cyclopropanecarboxylic acid methoxy-methyl-amide as a yellowish solid (0.96 g, 100%). LC-MS: MH+: 245.12, 72% AP.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]>>[OH:12][C:5]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=2)[NH:7][C:6]1=[O:11]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: Cc1ccccc1Br
Product: Cc1ccccc1C1(O)C(=O)Nc2ccc(I)cc21

Procedure:
With 5.46 g of 5-iodoisatin and 1-bromo-2-methyl benzene as starting materials, 5.87 g of the title compound (brown solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])(=O)[CH3:2].Cl.[CH2:13]([O:20][NH2:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>CO>[CH2:13]([O:20][N:21]=[C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])[CH3:2])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NOCc1ccccc1
Reactant: CC(=O)c1cccc(C#N)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CC(=NOCc1ccccc1)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 95 %

Procedure:
To a suspension of 14.52 g (0.10 mol) of 3-acetylbenzonitrile in 100 ml of methanol was added 17.56 g (0.11 mol) of O-benzylhydroxyamine hydrochloride and further added dropwise 9.49 g (0.12 mol) of pyridine. The mixture was stirred at room temperature for 2.5 hours, and most of the methanol was distilled off. To the residue was added ethyl acetate and resultant mixture was washed successively with about 5% aqueous hydrochloric acid twice, an about 5% aqueous solution of sodium bicarbonate once, and water once, then dried and concentrated to obtain 24.15 g (95.0 mmol) of crude 3-(1-(benzyloxyimino)ethyl)benzonitrile.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][CH2:13][C:14]([C:16]2[CH:25]=[CH:24][C:23]3[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20][C:19]([CH3:29])([CH3:28])[C:18]=3[CH:17]=2)=O)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[Cl-].[NH4+:32]>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:32][C:14]([C:16]3[CH:25]=[CH:24][C:23]4[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20][C:19]([CH3:29])([CH3:28])[C:18]=4[CH:17]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: [NH4+]
Reactant: COC(=O)c1ccc(C(=O)CCC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)[nH]2)cc1
Yield: 46.4 %

Procedure:
8.0 g (20 millimoles) of 1-(4-carbomethoxyphenyl)-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-butane-1,4-dione (for preparation see Example 9) and 5.5 g (0.1 mole) of ammonium chloride in 150 ml of dry dimethylformamide were heated for 6 hours at 150° C. After cooling, the mixture was poured onto water and the precipitated crystals were filtered off under suction, washed several times with water and dried in a stream of nitrogen. Purification by column chromatography (silica gel; n-heptane plus increasing amounts of ethyl acetate) and recrystallization from ethanol gave 3.6 g of the title compound of melting point 76°-179° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C@H:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)[CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[C:1]([O:5][C:6](=[O:33])[NH:7][C@H:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][S:42]([CH3:41])(=[O:44])=[O:43])=[CH:28][CH:27]=1)[CH2:9][N:10]1[CH2:11][CH2:12][CH:13]([C:16](=[O:24])[C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[CH2:14][CH2:15]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(N)cc1)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(NS(C)(=O)=O)cc1)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ((R)-1-(4-amino-benzyl)-2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-ethyl)-carbamic acid tert-butyl ester (1.19 g, 2.61 mmol) in dichloromethane (15 ml) cooled to 0° C. is added triethylamine (0.37 ml, 2.65 mmol) and methanesulfonylchloride (0.192 ml, 2.49mmol). The reaction mixture is allowed to warm to ambient temperature with stirring for 1 hour, then washed with water and saturated brine solution, dried over magnesium sulphate and evaporated. The crude product is purified by flash silica chromatography (ethylacetate:hexane gradient 6:4 to 1:0 elution) to afford [(R)-2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-1-(4-methanesulfonylamino-benzyl)-ethyl]-carbamic acid tert-butyl ester. [MH]+534.7.
Reaction SMILES: [C:1]1([CH:11]=[CH:12][CH2:13]Cl)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[S:17][C:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23][C:24]=2[N:25]=1.C(Cl)(Cl)Cl.CO>C(Cl)(Cl)Cl>[NH2:15][C:16]1[S:17][C:18]2[CH2:19][CH2:20][N:21]([CH2:13][CH:12]=[CH:11][C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[CH2:22][CH2:23][C:24]=2[N:25]=1
Reactant: ClCC=Cc1cccc2ccccc12
Reactant: Nc1nc2c(s1)CCNCC2
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Nc1nc2c(s1)CCN(CC=Cc1cccc3ccccc13)CC2
Yield: 31 %

Procedure:
Prepared from 3-(1-naphthyl)allyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6 H-thiazolo[5,4-d]azepine in chloroform for 3 days at 20° C. Yield: 31% of theory, Melting point: 178°-180° C. (chloroform/methanol =100:1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([OH:11])=[N:5][NH:6]2.C(=O)([O-])[O-].[K+].[K+].[C:18]([O:24][C@@H:25]1[C@@H:30]([O:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[C@H:29]([O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C@@H:28]([CH2:45][O:46][C:47](=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49])[O:27][C@@H:26]1Br)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].O>C(#N)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([O:11][C@@H:26]1[O:27][C@H:28]([CH2:45][O:46][C:47](=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49])[C@@H:29]([O:38][C:39](=[O:44])[C:40]([CH3:41])([CH3:42])[CH3:43])[C@H:30]([O:31][C:32](=[O:37])[C:33]([CH3:34])([CH3:35])[CH3:36])[C@H:25]1[O:24][C:18](=[O:23])[C:19]([CH3:22])([CH3:20])[CH3:21])=[N:5][NH:6]2
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@H](Br)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Reactant: Oc1n[nH]c2cccc(Br)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3cccc(Br)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C

Procedure:
A mixture of 4-bromo-1H-indazol-3-ol (1.27 g), potassium carbonate (1.65 g) and 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (which can be prepared in a manner described in literature, for example, Liebigs Ann. Chem. 1982, pp. 41-48; J. Org. Chem. 1996, vol. 61, pp. 9541-9545) (4.15 g) in acetonitrile (20 mL) was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethylether. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=5/1-2/1) to give the title compound (2.04 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]4[CH:25]=[CH:24]C([N+]([O-])=O)=C[CH:21]=4)=[O:18])[CH2:13][CH2:12]3)=[N:7][C:6]=12.[O:29]1CC[C@@H](O)C1.[H-].[Na+]>C1COCC1.CCOC(C)=O>[O:29]1[CH2:24][CH2:25][C@@H:20]([O:19][C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:8]3[CH:9]=[CH:10][N:5]4[N:4]=[CH:3][C:2]([Br:1])=[C:6]4[N:7]=3)[CH2:12][CH2:13]2)=[O:18])[CH2:21]1
Reactant: O[C@@H]1CCOC1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O[C@@H]1CCOC1)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
To 112 mg (0.25 mmol) of 4-nitrophenyl 4-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate dissolved in 10 mL of THF, was added (R)-tetrahydrofuran-3-ol (44 mg, 0.5 mmol), followed by 60% NaH (40 mg, 1.0 mmol) and stirred at RT for 2 hr. After 2 hr it was diluted with 20 mL of EtOAc and slowly quench with brine. The organic layer was dried over MgSO4 and concentrated, it was purified over 12 gram silica gel column eluting with 0-10% MeOH/DCM to obtain 71 mg (72% yield) of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])C=O.[CH:11](OC)([O:14][CH3:15])[O:12][CH3:13]>>[CH3:13][O:12][CH:11]([O:14][CH3:15])[C:4]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Br:1])[CH:3]=1
Reactant: O=Cc1ccc(Cl)c(Br)c1
Reactant: COC(OC)OC
Product: COC(OC)c1ccc(Cl)c(Br)c1

Procedure:
A solution of 6.8 g of 3-bromo-4-chlorobenzaldehyde in 17 ml of trimethyl orthoformate was stirred with 6.9 g of Amberlyst 15 resin at room temperature overnight. The mixture was filtered and the filtrate was evaporated to give 4.5 g of 3-bromo-4-chlorobenzaldehyde dimethyl acetal as a colourless oil, mass spectrum (EI) m/e 266 [M+].
Reaction SMILES: Cl[CH2:2][CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:11]1([O-:22])[C:16]([Cl:17])=[C:15]([Cl:18])[C:14]([Cl:19])=[C:13]([Cl:20])[C:12]=1[Cl:21].[Na+].O.C(O)C>C(O)C>[Cl:17][C:16]1[C:15]([Cl:18])=[C:14]([Cl:19])[C:13]([Cl:20])=[C:12]([Cl:21])[C:11]=1[O:22][CH2:2][CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: ClCC=Cc1ccccc1
Reactant: [O-]c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Clc1c(Cl)c(Cl)c(OCC=Cc2ccccc2)c(Cl)c1Cl
Yield: 85 %

Procedure:
In a 500 ml four necked flask equipped with a stirrer, a thermometer and a nitrogen gas inlet, chloromethylstyrene (m/p=60/40) (25 g, 0.161 mole) was dissolved in ethanol (50 ml) at room temperature. A solution of sodium pentachlorophenate (hereinafter abbreviated as Na-PCP) (49 g. 0.170 mole) in a mixed solvent of water/ethanol (1/1, 250 ml) was gradually added dropwise thereto and, after completion of addition, the mixture was reacted at 50° C. for 1 hour. The mixture was cooled and the resulting precipitate was filtered off. The filtrate was concentrated with a rotary evaporator. Then, n-hexane (250 ml) and distilled water (100 ml) were added to the concentrated solution and the mixture was shaken. The aqueous layer was removed and additional distilled water (100 ml) was added. This procedure was repeated to remove unreacted Na-PCP. The hexane layer was evaporated with a rotary evaporator. Then, the solid residue was recrystallized from acetone to obtain (2, 3, 4, 5, 6-pentachlorophenyloxy)methylstyrene of the formula [Ia] as white needle crystals, m.p. 113°-115° C., yield 85%.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].CCN(C(C)C)C(C)C.[N:23]1([C:29](=[O:31])[CH3:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(#N)C>[C:29]([N:23]1[CH2:28][CH2:27][N:26]([CH:2]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:25][CH2:24]1)(=[O:31])[CH3:30]
Reactant: CC(=O)N1CCNCC1
Reactant: CCOC(=O)C(Br)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C(c1ccccc1)N1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
Ethyl 2-bromo-2-phenylacetate (0.22 ml, 1.23 mmol) was dissolved in acetonitrile (4 ml) and DIPEA (0.28 ml, 1.60 mmol) and 1-(piperazin-1-yl)ethanone (0.21 g, 1.60 mmol) were sequentially added. The reaction was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by flash chromatography (DCM/Acetone=9/1) to obtain ethyl 2-(4-acetylpiperazin-1-yl)-2-phenylacetate (341 mg, 95% yield) as a pale yellow oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21].[CH2:24]([C:28]1[N:29]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[C:30]([CH:33]=[O:34])=[CH:31][N:32]=1)[CH2:25][CH2:26][CH3:27]>O1CCCC1>[CH2:24]([C:28]1[N:29]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[C:30]([CH:33]([OH:34])[CH:19]([CH2:18][C:14]2[S:13][CH:17]=[CH:16][CH:15]=2)[C:20]([O:22][CH3:23])=[O:21])=[CH:31][N:32]=1)[CH2:25][CH2:26][CH3:27]
Reactant: COC(=O)CCc1cccs1
Reactant: CCCCc1ncc(C=O)n1Cc1ccccc1Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCCc1ncc(C(O)C(Cc2cccs2)C(=O)OC)n1Cc1ccccc1Cl
Reaction time: 0.17 h
Yield: 81.2 %

Procedure:
To a solution of diisopropylamine (1.96 g, 0.0194 mol) in dry tetrahydrofuran (40 mL) held at -78° C. under argon was added n-butyl lithium (7.3 mL, 0.0183 mol of 2.5M in toluene), and the mixture was stirred for 10 minutes. Then, methyl 3-(2-thienyl)propanoate (2.83 g, 0.0166 mol) in tetrahydrofuran (2 mL) was added, and the mixture was stirred for 30 minutes at -78° C. A solution of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde (3 g, 0.0111 mol) in tetrahydrofuran (4 mL) was added, and the resulting mixture was stirred at -78° C. for 30 minutes. The reaction was partitioned between saturated ammonium chloride solution and ether, the organic extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated to 6.67 g of crude product. This was flash chromatographed over 70 g of silica gel with 4:1 ethyl acetate/hexanes to provide 4.03 g (81%) of methyl 3-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-yl]-3-hydroxy-2-[(2-thienyl)methyl]propanoate.
Reaction SMILES: [C:1]1([S:7]([Cl:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH2:13]1[C:23]2=[C:24]3[C:19](=[CH:20][CH:21]=[CH:22]2)[CH2:18][CH2:17][N:16]([CH2:25][CH2:26][CH2:27][NH:28][C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)[CH:15]3[CH2:14]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[ClH:10].[CH2:13]1[C:23]2=[C:24]3[C:19](=[CH:20][CH:21]=[CH:22]2)[CH2:18][CH2:17][N:16]([CH2:25][CH2:26][CH2:27][N:28]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)[S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:15]3[CH2:14]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cccc(NCCCN2CCc3cccc4c3C2CC4)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc(N(CCCN2CCc3cccc4c3C2CC4)S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.6 %

Procedure:
Benzenesulfonyl chloride (48.6 mg, 0.28 mmol) was added to a solution of [3-(2,2a,4,5-Tetrahydro-1H-3-aza-acenaphthylen-3-yl)-propyl]-m-tolyl-amine dihydro-chloride (43.0 mg, 0.11 mmol) and N,N′-diisopropylethylamine (2 ml) in CH2Cl2 (2 mL) and the mixture was stirred overnight at room temperature. The resulting solution was washed with water (3×10 ml), dried over Na2SO4 and evaporated to dryness. The free base was dissolved in ethyl acetate (1 ml). A 2.8 M solution of hydrogen chloride in ethanol (0.10 mL) was then added. The product was crystallized and collected by filtration, and vacuum dried to give a white solid (20.0 mg, 36% yield).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].[CH2:10](O)[CH2:11][CH2:12]CCCCC>S(=O)(=O)(O)O.O.C1(C)C=CC=CC=1>[C:7]([OH:9])(=[O:8])[CH2:2][CH2:3][CH2:5][CH2:6][CH2:10][CH2:11][CH3:12].[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: CCCCCCCCO
Agent: CC[C@H](C)[C@H](N)C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCC(=O)O
Temperature: 25 °C

Procedure:
13.1 g of isoleucine was dissolved in a solution of 10 g of concentrated sulfuric acid, 20 mL water, 20 mL of octanol, and 200 mL of toluene in a 500 mL round bottom flask equipped with a condenser and a Dean-Stark apparatus placed in an oil bath. The resulting solution was heated at reflux temperature until no more water could be distilled. The resulting solution was then cooled to room temperature, diluted with 120 mL of ethyl acetate and the organic layer washed with saturated aqueous sodium bicarbonate to neutralize acidic impurities, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the resulting liquid distilled to provide isoleucine octanoate as a colorless liquid.
Reaction SMILES: C(N(CC)CC)C.C(O[CH:13]=[CH:14][C:15](=O)[C:16]([O:18][CH3:19])=[O:17])CCC.Cl.[NH2:22][C:23]([NH2:25])=[NH:24]>C(#N)CC>[NH2:25][C:23]1[N:24]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[CH:13][N:22]=1
Reactant: N=C(N)N
Reactant: CCCCOC=CC(=O)C(=O)OC
Agent: Cl
Solvent: CCC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccnc(N)n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
Triethylamine (29 mL, 210 mmol) was added to a suspension of methyl 4-butoxy-2-oxo-3-butenate (37 g, 200 mmol, JP-A-2003-89690) and guanidine hydrochloride (23 g, 240 mmol) in propionitrile (50 mL), and the mixture was stirred for 4 hours at 100° C. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 18 g as the mixture of the title Reference Compound and the butyl ester form of the title Reference compound as a gray-white solid (Yield: 60%).
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:1][C@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Reactant: Oc1ccccc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](Oc3ccccc3F)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 53.8 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 2-fluorophenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (3.5 mg, 53.9% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.65 (m, 1H), 7.41 (s, 1H), 7.40-7.10 (m, 5H), 7.05 (m, 2H), 6.97 (apparent d, 1H, J=8.7 Hz), 6.86 (m, 2H), 6.79 (apparent dt, 1H, J=2.4, 7.9 Hz), 5.31 (apparent dd, 1H, J=4.5, 8.0 Hz), 3.39 (m, 2H), 2.97 (m, 2H), 2.53 (apparent sept, partially hidden, 2H, J=7.5 Hz), 2.3-2.1 (m, 6H), 1.92 (m, 2H), 1.25 (d, 6H, J=6.7 Hz); ESMS m/e: 475.7 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([NH:9][C:10]([C:12]1[CH:21]=[C:20]([Cl:22])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[O:23][CH2:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:11])([CH3:8])[CH2:6][CH3:7])[CH3:2].[C:32](Cl)(=[O:34])[CH3:33].CCN(CC)CC>ClCCl>[CH2:1]([O:3][C:4](=[O:31])[C:5]([NH:9][C:10]([C:12]1[CH:21]=[C:20]([Cl:22])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[O:23][CH2:24][CH:25]1[CH2:26][CH2:27][N:28]([C:32](=[O:34])[CH3:33])[CH2:29][CH2:30]1)=[O:11])([CH3:8])[CH2:6][CH3:7])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C(C)(CC)NC(=O)c1cc(Cl)c2ccccc2c1OCC1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(CC)NC(=O)c1cc(Cl)c2ccccc2c1OCC1CCN(C(C)=O)CC1
Reaction time: 8 h

Procedure:
To a solution of 70 mg of 2-{[4-chloro-1-(piperidin-4-yl-methoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-butyric acid ethyl ester in 4 mL dichloromethane was added 0.026 ml of acetyl chloride followed by addition of 0.13 mL Et3N. This mixture was stirred overnight. The mixture was concentrated and chromatographed on silica with 7 N NH3 in MeOH/dichloromethane to give 76 mg of 2-{[1-(1-acetyl-piperidin-4-ylmethoxy)-4-chloro-naphthalene-2-carbonyl]-amino}-2-methyl-butyric acid ethyl ester.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]2[CH2:5][C:6]3[N:11]4[CH:12]=[CH:13][N:14]=[C:10]4[C:9](=[O:15])[NH:8][C:7]=3[C:16]=2[CH:17]=[CH:18][CH:19]=1.[CH3:20][NH:21][C:22](=O)[O:23]C1C=CC([N+]([O-])=O)=CC=1>CN(C)C=O>[CH3:20][NH:21][C:22](=[O:23])[NH:1][CH2:2][C:3]1[C:4]2[CH2:5][C:6]3[N:11]4[CH:12]=[CH:13][N:14]=[C:10]4[C:9](=[O:15])[NH:8][C:7]=3[C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: NCc1cccc2c1Cc1c-2[nH]c(=O)c2nccn12
Reactant: CNC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: CNC(=O)NCc1cccc2c1Cc1c-2[nH]c(=O)c2nccn12
Temperature: 20 °C
Reaction time: 4 h
Yield: 65.2 %

Procedure:
A suspension of 0.25 g of 9-aminomethyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 0.49 g of 4-nitrophenyl N-methylcarbamate and 10 ml of dimethylformamide under an argon atmosphere is stirred for 4 hours at a temperature in the region of 20° C. The reaction mixture is filtered, washed successively with 5 ml of dimethylformamide and two times 20 ml of methyl-tert-butyl ether and then dried under reduced pressure (1 mm Hg; 0.13 kPa) at 60° C. 0.2 g of 9-[(3-methylureido)methyl]-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one is obtained in the form of a white solid, the melting point of which is greater than 260° C. (Analysis C16H15N5O2; % Calculated C: 62.13, H: 4.89, N: 22.64; % Found C: 62.03, H: 4.90, N: 22.26).
Reaction SMILES: Cl.[N:2]1([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:34][CH:35]1[CH2:37][CH2:36]1.O>CN(C)C=O>[CH:35]1([CH2:34][N:5]2[CH2:6][CH2:7][N:2]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=4)[N:9]=3)[CH2:3][CH2:4]2)[CH2:37][CH2:36]1
Reactant: FC(F)(F)c1ccc(-n2nc(N3CCNCC3)c3ccccc32)cc1
Reactant: ClCC1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc(-n2nc(N3CCN(CC4CC4)CC3)c3ccccc32)cc1
Yield: 51.6 %

Procedure:
A stirred mixture of 5.0 g of 3-(1-piperazinyl)-1-[4-(trifluoromethyl)phenyl]-1H-indazole hydrochloride, 2.2 g of potassium carbonate, and 1.4 g of chloromethylcyclopropane in 50 ml of dimethylformamide was heated at 85°-90° for 20 hours. The reaction mixture was poured into water and the aqueous suspension extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated to an oil. The oil was flash chromatographed on silica gel utilizing ethyl acetate as the eluent. Concentration of the appropriate fractions gave 2.7 g (48%) of 3-[4-(cyclopropyl)methyl-1-piperazinyl]-1-[4-(trifluoromethyl)phenyl]-1H-indazole, mp 98°-100°.