Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]3[CH2:11][CH2:12][NH:13][C:7]3([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=3)[CH2:6][N:5]2[CH:22]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[OH:21][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:7]23[NH:13][CH2:12][CH2:11][N:8]2[C:9](=[O:10])[C:4]2[N:5]([CH:22]=[C:2]([C:25]4[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=4)[CH:3]=2)[CH2:6]3)=[CH:19][CH:18]=1
Reactant: O=C1c2cc(Br)cn2CC2(c3ccc(CO)cc3)NCCN12
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: O=C1c2cc(-c3cccnc3)cn2CC2(c3ccc(CO)cc3)NCCN12
Temperature: 120 °C
Reaction time: 0.75 h
Yield: 96.5 %

Procedure:
7-bromo-10a-[4-(hydroxymethyl)phenyl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (84 mg, 0.23 mmol), dichlorobis(triphenylphosphine)palladium(II) (6.5 mg, 9.3 μmol), 3-pyridine boronic acid (34 mg, 0.28 mmol) and an aqueous solution of sodium carbonate (2M) (58 mg, 28.8 μl, 0.41 mmol) were suspended in a mixture of 1,2-dimethoxyethane (2.5 mL), ethanol (200 μL) and water (300 μL). The reaction vessel was flushed with argon and heated at 120° C. After 45 minutes the reaction was complete. The mixture was diluted with CH2Cl2 (5 mL) then washed with H2O. The aqueous was extracted with CH2Cl2 (2×5 mL). The combined organic was evaporated to dryness to give crude 10a-[4-(hydroxymethyl)phenyl]-7-(pyridin-3-yl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (80 mg) that was used in the next step without further purification. ESI-MI m/z [M+H]+ 361.9.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1.[CH2:13]([N:15]([CH2:26][CH3:27])[CH2:16][CH2:17][O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)[CH3:14]>C1COCC1.CC(O)C>[CH2:26]([N:15]([CH2:13][CH3:14])[CH2:16][CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([NH:23][C:2]2[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=2)=[CH:24][CH:25]=1)[CH3:27]
Reactant: CNc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: CCN(CC)CCOc1ccc(N)cc1
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CCN(CC)CCOc1ccc(Nc2ncc([N+](=O)[O-])c(NC)n2)cc1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
To a solution of 1.89 g (10 mmol) of 2-chloro-4-(methylamino)-5-nitropyrimidine in 100 mL THF at −78° C. is added a solution of 2.48 g (12 mmol) of 4-[2-(diethylamino)ethoxy]aniline in 100 mL of 2-propanol, and the resulting mixture is allowed to warm slowly to room temperature. The precipitate is collected, washed with 2-propanol, and dissolved in water. After being filtered through celite, the aqueous solution is basified with aqueous ammonia, and the resulting precipitate is collected, washed with water, and dried, to give 2.88 g (80%) of the title compound: mp (EtOH)163–164° C.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[CH2:7]([C:9]1[C:20]([CH:21](O)[CH3:22])=[C:12]2[C:13]3[CH2:19][CH2:18][O:17][C:14]=3[CH:15]=[CH:16][N:11]2[N:10]=1)[CH3:8].C(=O)([O-])O.[Na+]>ClC1C=CC=CC=1>[CH2:7]([C:9]1[C:20]([CH:21]([CH3:22])[C:5]#[N:6])=[C:12]2[C:13]3[CH2:19][CH2:18][O:17][C:14]=3[CH:15]=[CH:16][N:11]2[N:10]=1)[CH3:8]
Reactant: C[Si](C)(C)C#N
Reactant: CCc1nn2ccc3c(c2c1C(C)O)CCO3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Clc1ccccc1
Product: CCc1nn2ccc3c(c2c1C(C)C#N)CCO3
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.8 %

Procedure:
Under an argon atmosphere, to a solution of boron trifluoride diethyl ether complex (0.411 mL, 3.24 mmol) and trimethylsilyl cyanide (0.576 mL, 4.32 mmol) in chlorobenzene (10 mL) was added a solution of 1-(2-ethyl-8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridin-1-yl)ethanol (250 mg, 1.08 mmol) in chlorobenzene (20 mL) under ice-cooling, and the mixture was stirred at room temperature for 15 min. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→40/60) to give the title compound (195 mg, yield 75%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CCN(C2N=CC(Br)=CN=2)CC1)=O)(C)(C)C.[F:47][C:48]([F:59])([F:58])C1C=CC(B(O)O)=CC=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:48]([F:59])([F:58])[F:47])=[CH:22][CH:21]=3)=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1
Agent: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3ccc(C(F)(F)F)cc3)cn2)CC1
Yield: 95 %

Procedure:
Prepared according to the method for the preparation of 4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-carboxylic acid tert-butyl ester, from 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (0.346 g) and 4-(trifluoromethyl)benzeneboronic acid (0.211 g), to yield the title compound as a grey solid (0.392 g, 95%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][NH2:19])=[S:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23]([N:25]=[C:26]=[O:27])[CH3:24]>>[CH2:23]([NH:25][C:26]([NH:19][NH:18][C:16]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]1[CH:20]=[CH:21][CH:22]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1)=[S:17])=[O:27])[CH3:24]
Reactant: CCN=C=O
Reactant: NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1
Product: CCNC(=O)NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1

Procedure:
The compound is prepared by a method analogous to that of Example 9 from N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-hydrazine carbothioamide and ethyl isocyanate. The analytical values are summarized in Table I.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:28]=[CH:29][CH:30]=1)[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][CH2:20][C:18]2=[O:19])[CH2:13][CH2:12]1)=[O:10])=O)C.[NH3:31].[Cl-].[NH4+]>C(O)C>[C:4]([C:6]1[CH:7]=[C:8]([CH:28]=[CH:29][CH:30]=1)[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][CH2:20][C:18]2=[O:19])[CH2:13][CH2:12]1)=[O:10])(=[O:3])[NH2:31]
Reactant: CCOC(=O)c1cccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)c1
Reactant: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: NC(=O)c1cccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)c1
Temperature: 120 °C
Reaction time: 10 h

Procedure:
1-[1-(3-Ethoxycarbonylbenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (0.5 g), aqueous ammonia (10 ml) and ammonium chloride (the effective amount as a catalyst) are dissolved in ethanol (10 ml) and the mixture is stirred at 110-130° C. for 10 hours in an autoclave. Ethanol is distilled off under reduced pressure and the residue is extracted with methylene chloride. The organic layer is washed with water and saturated saline solution, dried with sodium sulfate and concentrated. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (solvent: methylene chloride:methanol=10:1) to give 1-[1-(3-carbamoylbenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (0.15 g).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[NH2:8][C:9]([NH2:11])=[NH2+:10].[CH:12]([N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]1[CH2:25][C:26](OCC)=[O:27])([CH3:14])[CH3:13]>O>[CH:12]([N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]1[CH2:25][C:26]([NH:10][C:9]([NH2:11])=[NH:8])=[O:27])([CH3:14])[CH3:13]
Reactant: CCOC(=O)CC1c2ccccc2C(=O)N1C(C)C
Reactant: NC(N)=[NH2+]
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: CC(C)N1C(=O)c2ccccc2C1CC(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 20 h
Yield: 6.8 %

Procedure:
N-[(2-Isopropyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine is prepared as described in Example 1, starting with 1.5 g of potassium tert-butoxide, 1.3 g of guanidinium chloride and 0.7 g of ethyl (2-isopropyl-3-oxo-2,3-dihydro-1H-isoindol1-yl)acetate. The reaction mixture is stirred at a temperature in the region of 20° C. for 20 hours, followed by addition of 30 cm3 of water. The aqueous phase is extracted with 3 times 50 cm3 of ethyl acetate and is then concentrated to dryness under reduced pressure (0.6 kPa) at a temperature in the region of 45° C. The residue is taken up in water, triturated and filtered. The solid is taken up in a mixture of dichloromethane/methanol (90/10 by volume) and filtered, and the filtrate is purified by chromatography under argon pressure (60 kPa), on a column of silica gel (particle size 15-40 μm), eluting with a dichloromethane/methanol mixture (90/10 by volume). The fractions comprising the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 0.05 g of N-[(2isopropyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine is thus obtained in the form of a white solid. Mass spectrum EI: m/e 274 (M+), m/e 187, m/e 132. Infrared spectrum (KBr): 3412; 1974; 1667; 1603; 1531; 1367 and 698 cm−1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:7][O:8][C:9]=1[C:10]([OH:12])=O)=[O:4].O[N:20]=[C:21]([C:23]1[CH:40]=[CH:39][C:26]([CH2:27][N:28]2[CH2:31][CH:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]2)=[CH:25][CH:24]=1)[NH2:22].N1C=CC=CC=1C1C(C(F)(F)F)=C(C2ON=C(C3C=CC(CN4CC(C(O)=O)C4)=CC=3)N=2)ON=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C>CN(C)C=O>[C:35]([O:34][C:32]([CH:30]1[CH2:31][N:28]([CH2:27][C:26]2[CH:39]=[CH:40][C:23]([C:21]3[N:22]=[C:10]([C:9]4[O:8][N:7]=[C:6]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=5)[C:5]=4[C:3]([O:2][CH3:1])=[O:4])[O:12][N:20]=3)=[CH:24][CH:25]=2)[CH2:29]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(C(N)=NO)cc2)C1
Reactant: COC(=O)c1c(-c2ccccn2)noc1C(=O)O
Agent: O=C(O)C1CN(Cc2ccc(-c3noc(-c4onc(-c5ccccn5)c4C(F)(F)F)n3)cc2)C1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1c(-c2ccccn2)noc1-c1nc(-c2ccc(CN3CC(C(=O)OC(C)(C)C)C3)cc2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
To a mixture of 4-(methoxycarbonyl)-3-(pyridin-2-yl)isoxazole-5-carboxylic acid (79 mg, 0.318 mmol), tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate, Int. 1 (97 mg, 0.318 mmol), and BOP—Cl (97 mg, 0.382 mmol) in dimethylformamide (1.5 mL) at room temperature was added triethylamine (0.133 mL, 0.955 mmol). The reaction mixture was allowed to stir at room temperature overnight. Some uncyclized material remained, so stirring was continued for an additional 24 hrs. At this time, the reaction mixture was partitioned between ethyl acetate (30 mL) and a saturated aqueous solution of sodium bicarbonate (30 mL). The organic layer was washed with water (2×30 mL), washed with brine (30 mL), and dried over anhydrous magnesium sulfate. Concentration afforded a brown oil that was chromatographed on a 4 gm Isco silica gel cartridge, eluting with a 0-70% EtOAc/Hex gradient. The essentially pure fractions containing product were concentrated to afford methyl 5-(3-(4-((3-(tert-butoxycarbonyl)azetidin-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)-3-(pyridin-2-yl)isoxazole-4-carboxylate (80 mg, 0.155 mmol, 48.6% yield) as a light purple solid. HPLC retention time=2.91 minutes (YMC-Combi 4.6×50 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS: (M+H)=518.20.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:9](=O)[CH2:8][S:7][CH2:6]1)=[O:4].Cl.[NH2:12][OH:13].C(=O)([O-])[O-].[Ba+2]>CO>[CH3:1][O:2][C:3]([CH:5]1[C:9](=[N:12][OH:13])[CH2:8][S:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CSCC1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: COC(=O)C1CSCC1=NO
Yield: 98.5 %

Procedure:
A suspension of 4-oxo-tetrahydro-thiophene-3-carboxylic acid methyl ester (33) (16.96 g, 106 mmol), hydroxylamine hydrochloride (16.96 g, 244 mmol) and barium carbonate (48.16 g, 244 mmol) in methanol (800 mL) was refluxed overnight. The solution was cooled and filtered. The filtrate was concentrated in vacuo. The residue was suspended in water and extracted by ethyl acetate. The combined organic phase was dried over MgSO4 and concentrated to yield 18.30 g (98%) of an isomeric mixture of 4-hydroxyimino-tetrahydro-thiophene-3-carboxylic acid methyl ester as a viscous oil. 1H NMR (400 MHz, CDCl3) δ 3.14-4.11 (m, 7H), 8.17 (m, 1H) ppm. The isomeric mixture was used in the following step without further purification.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[N:14]=[N:15]NN=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](Cl)(=[O:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.O.[OH-].[Na+]>N1C=CC=CC=1>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[O:28][C:18]([C:19]4[CH:27]=[CH:26][C:22]([C:23]5[O:24][C:13]([C:9]6[N:8]=[C:7]([C:1]7[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=7)[CH:12]=[CH:11][CH:10]=6)=[N:14][N:15]=5)=[CH:21][CH:20]=4)=[N:15][N:14]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Reactant: c1ccc(-c2cccc(-c3nn[nH]n3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: c1ccc(-c2cccc(-c3nnc(-c4ccc(-c5nnc(-c6cccc(-c7ccccc7)n6)o5)cc4)o3)n2)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 58 %

Procedure:
5.0 g of 2-phenyl-6-(2H-tetrazol-5-yl)pyridine was dissolved in 125 ml of dehydrated pyridine. Temperature was elevated to 120° C., and 75 ml was dehydrated by azeotropy. After cooling to 50° C., 2.30 g of terephthaloyl dichloride was added. Temperature was elevated to 100° C., and stirring was conducted for 5 hours. After cooling to room temperature, the reaction solution was poured into 300 ml water, and after adjusting pH to 12 with 20% sodium hydroxide aqueous solution, stirring was conducted for 1 hour. A precipitated yellow solid was taken out by suction filtration, and washed with water. The solid obtained was vacuum dried at 70° C. for 20 hours, and purified with dispersion washing by a chloroform-methanol mixed solution to obtain 3.40 g (yield 58%) of PhpyOXDp. The product was identified with NMR analysis. The result of NMR analysis (CDCl3) was as follows. 8.45 ppm (4H), 8.29 ppm (2H), 8.16 ppm (4H), 7.93-8.02 ppm (4H), 7.50-7.59 ppm (6H).
Reaction SMILES: [NH2:1][C:2]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)[CH2:4][CH:3]1[CH2:5][OH:6].C(N(C(C)C)CC)(C)C.Cl[C:26]([O:28][CH3:29])=[O:27]>ClCCl>[OH:6][CH2:5][CH:3]1[CH2:4][C:2]1([NH:1][C:26](=[O:27])[O:28][CH3:29])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1
Reactant: NC1(c2cccc([N+](=O)[O-])c2)CC1CO
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)NC1(c2cccc([N+](=O)[O-])c2)CC1CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.4 %

Procedure:
Step b) To a solution of ((1RS,2SR)-2-amino-2-(3-nitrophenyl)cyclopropyl)methanol (2.85 g, 13.7 mmol, Eq: 1.00) in dichloromethane (27.4 ml) was added at 5° C. diisopropylethylamine (2.65 g, 3.59 ml, 20.5 mmol, Eq: 1.5) and methyl chloroformate (1.42 g, 1.17 ml, 15.1 mmol, Eq: 1.1) dropwise via syringe. The reaction mixture was stirred at rt for 16 hours. The reaction mixture was extracted with sat NaHCO3 solution and dichloromethane. The organic layer was washed with water and brine, the aqueous layers were reextracted with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and evaporated to give a brown oil which was purified by silica gel flash chromatography with 0-100% EtOAc in heptane to give the title methyl (1SR,2RS)-2-(hydroxymethyl)-1-(3-nitrophenyl)cyclopropylcarbamate (3.52 g, 13.2 mmol, 96.6% yield) as a light brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([CH3:16])[CH3:15])[C:5]([O:17]C)=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH:25]([CH3:27])[CH3:26])[CH:3]=1.O.C(OCC)C>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([CH3:16])[CH3:15])[C:5]([OH:17])=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH:25]([CH3:27])[CH3:26])[CH:3]=1
Reactant: COc1c(-c2ccccc2C(C)C)cc(C)cc1-c1ccccc1C(C)C
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cc(-c2ccccc2C(C)C)c(O)c(-c2ccccc2C(C)C)c1
Yield: 95 %

Procedure:
A mixed solution of 1 mL of water and 4 mL of dimethoxyethane was added into a flask into which 2,6-dibromo-4-methylanisole (400 mg, 1.43 mmol), 2-isopropylphenylboronic acid (720 mg, 4.39 mmol), palladium acetate (14 mg, 0.062 mmol), triphenylphosphine (60 mg, 0.23 mmol), and potassium phosphate (940 mg, 4.43 mmol) were already added, and then refluxed at normal temperature for 6 hours. After cooling to normal temperature, an ammonium chloride aqueous solution (5 mL) and 10 mL of diethylether were added thereto to separate an organic layer and extract residues using diethylether. The separated organic layer was dried with magnesium sulfate and volatile materials were then removed to produce 670 mg of grey 4-methyl-2,6-bis(2′-isopropylphenyl)anisole solid. The anisole thus produced was dissolved in 5 mL of methylene chloride without separate purification, 3 mL of boron tribromide (1 M methylene chloride solution) was dropped thereon at −78° C., and a reaction was carried out while the temperature was slowly increased to normal temperature. After the reaction, a mixed solution of water (5 mL) and diethylether (10 mL) was added to separate an organic layer and extract an aqueous solution layer using diethylether (5 mL×3), and the separated organic layer was dried. Residues from which volatile components were removed at reduced pressure were purified using a silica gel chromatography tube in a mixed solvent of hexane and methylene chloride to produce 0.47 g of white 4-methyl-2,6-bis(2′-isopropylphenyl)phenol solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.Cl.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[CH:39][CH:38]=1>C(#N)CC>[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([CH:43]2[CH2:44][CH2:45][N:46]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]5[C:7](=[O:17])[NH:6][C:5]=4[CH:4]=3)[CH2:47][CH2:48]2)=[CH:39][CH:38]=1
Reactant: Clc1ccc(C2CCNCC2)cc1
Reactant: O=C1Nc2cc(CO)cnc2N2CCCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Nc2cc(CN3CCC(c4ccc(Cl)cc4)CC3)cnc2N2CCCC[C@@H]12
Temperature: 90 °C
Reaction time: 16 h
Yield: 12.5 %

Procedure:
(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (100 mg, 0.429 mmol) was suspended in propionitrile (1 mL) and (cyanomethyl)trimethylphosphonium iodide (125.0 mg, 0.51 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (225 ul, 1.3 mmol). To the stirred mixture was then added 4-(4-chlorophenyl)piperidine hydrochloride (109 mg, 0.472 mmol). The reaction was heated to 90° C. with stirring for 16 h. The crude reaction was cooled to room temperature and concentrated to a residue, then taken up in 3 mL DMSO and purified via HPLC (55-90% acetonitrile in water, ammonium bicarbonate buffer). The fractions were combined and concentrated until a white solid precipitated. The precipitate was filtered off and dried in vacuum to afford the title compound (22.1 mg, 12.5%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.46 (s, 1H), 7.64 (d, J=2.0 Hz, 1H), 7.29-7.37 (m, 2H), 7.21-7.28 (m, 2H), 6.96 (d, J=2.0 Hz, 1H), 4.42-4.58 (m, 1H), 3.83 (dd, J=11.4, 2.8 Hz, 1H), 3.32 (s, 2H), 2.80-2.95 (m, 2H), 2.54-2.66 (m, 1H), 1.92-2.08 (m, 3H), 1.83 (br. s., 1H), 1.66-1.77 (m, 2H), 1.33-1.66 (m, 6H). [M+H] calc'd for C23H27ClN4O, 411. found, 411.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[NH2:20][CH2:21][C:22]([NH2:24])=[O:23]>>[C:22]([CH2:21][NH:20][C:17]([C:15]1[CH:16]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:12]=[N:13][CH:14]=1)=[O:19])(=[O:23])[NH2:24]
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: NCC(N)=O
Product: CCc1cc(-c2cncc(C(=O)NCC(N)=O)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and α-aminoacetamide to afford the title compound. MS: m/e=315 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.Cl[C:13]1C=CC=CC=1C(C)C(O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:13])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)c1ccccc1Cl
Reactant: O=C(O)Cc1ccc(Cl)cc1
Product: CC(C(=O)O)c1ccc(Cl)cc1
Yield: 73 %

Procedure:
The titled compound was prepared from p-chlorophenylacetic acid in 73% yield in the same manner as the preparation of 2-(2-Chlorophenyl)propionic acid in Example 184a. MS (ESI) 185 (MH+).
Reaction SMILES: [ClH:1].[CH:2]([C:5]1[CH:10]=[CH:9][C:8](NN)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C(OC(OCC)CCC[N:20]1[C:24](=O)[C:23]2=CC=C[CH:29]=[C:22]2C1=O)C.Cl.C([O-])(O)=O.[Na+].O.[NH2:41]N>C(O)C.C(Cl)Cl.O>[ClH:1].[CH:2]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[C:22]([CH2:23][CH2:24][NH2:20])=[CH:29][NH:41]2)([CH3:4])[CH3:3]
Reactant: CCOC(CCCN1C(=O)c2ccccc2C1=O)OCC
Reactant: CC(C)c1ccc(NN)cc1
Reactant: NN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CC(C)c1ccc2c(CCN)c[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-isopropylphenylhydrazine hydrochloride (660 mg, 3.55 mmol) and 4-phthalimidobutanal diethyl acetal (1.15 g, 3.95 mmol) in Ethanol (EtOH; 30 ml) was heated at 60° C. to 65° C. for 1 h with water (0.050 ml). The mixture was then treated with concentrated HCl (0.50 ml) and refluxed for 14 h. After concentrating the reaction, the residue was partioned in methylene chloride and saturated aqueous NaHCO3. The aqueous solution was extracted with methylene chloride (3 times) and the combined organic solutions were dried (MgSO4) and concentrated to give after chromatography (4:1 hexane-ethyl acetate) on silica gel 146 mg of product. The above product was treated with hydrazine hydrate (1 ml) in EtOH (4 ml) and water (1 ml) and stirred at RT overnight. After concentrating the reaction to an aqueous mixture, the product was extracted with methylene chloride (3 times). The combined organic solution was dried (MgSO4) and concentrated. The residue was redissolved in methylene chloride and treated with 1M HCl in ether. The precipitate was collected and washed with ether and hexane and dried to provide 102 mg of 6-isopropyltryptamine hydrochloride salt. This tryptamine obtained above was transformed into 7-isopropyl-β-carboline according to the procedure used in example 3. The hydrochloride salt was obtained by treating a solution of 7-Isopropyl-β-carboline in methylene chloride with 1M HCl in ether and concentrating. The residue was triturated with (1:1) methylene chloride-hexane to give 15 mg of 7-isopropyl-β-carboline hydrochloride.