Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C1(N=C=NC2CCCCC2)CCCCC1.[C:29]([NH2:33])([CH3:32])([CH3:31])[CH3:30]>N1C=CC=CC=1>[C:29]([NH:33][C:11]([C:10]1[CH:9]=[CH:8][CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]=1[OH:1])=[O:13])([CH3:32])([CH3:31])[CH3:30]
Reactant: O=C(O)c1cccc(C(=O)O)c1O
Reactant: CC(C)(C)N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CC(C)(C)NC(=O)c1cccc(C(=O)O)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Hydroxyisophthalic acid (1.82 g) and N,N'-dicyclohexylcarbodiimide (2.17 g) were dissolved together in dry pyridine (30 ml) and the mixture was stirred for 2 hours at room temperature. The mixture was then treated with dry tert-butylamine (5 ml), and the mixture was stirred at 60° C. for 20 hours. The solvents were removed in vacuo, and the residue was treated with saturated aqueous sodium bicarbonate solution (50 ml). The mixture was stirred for 15 minutes. The insoluble N,N'-dicyclohexylurea was then removed by filtration and the resulting filtrate was treated with charcoal and filtered again. The filtrate was then acidified by treatment with concentrated hydrochloric acid to give a white solid which was filtered off and recrystallized from a mixture of petroleum ether (b.p. 60°-80° C.) and benzene to give 3-tert-butylcarbamoylsalicylic acid (1.2 g), m.p. 191°-195° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12]>[Pd].CO.O1CCCC1>[NH2:8][C:7]1[C:2]([OH:1])=[C:3]([S:11]([N:14]([CH3:15])[CH3:16])(=[O:13])=[O:12])[CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)S(=O)(=O)c1cccc([N+](=O)[O-])c1O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)S(=O)(=O)c1cccc(N)c1O
Reaction time: 17 h
Yield: 106 %

Procedure:
104 mg (10% by weight) of palladium on carbon at 10% were added to a solution of 1.01 g (4.10 mmol) of 2-hydroxy-N,N-dimethyl-3-nitrobenzenesulfonamide in 20 ml of methanol and 20 ml of tetrahydrofuran. The reaction medium was stirred under a hydrogen atmosphere for 17 hours. The reaction medium was filtered through celite and was concentrated. 0.94 g of product was obtained in the form of a brown solid. Quantitative yield.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1.S(Cl)([Cl:18])=O.N1C=CC=CC=1.CCOCC>O1CCCC1>[Cl:18][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1ccc(CO)cc1[N+](=O)[O-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(CCl)cc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 98.8 %

Procedure:
A mixture of methyl 4-hydroxymethyl-2-nitrobenzoate (1.49 g), thionyl chloride (1.08 g), dry pyridine (0.1 g), dry ether (70 ml) and dry tetrahydrofuran (20 ml) was stirred overnight. The reaction mixture was washed in turn with 1N hydrochloric acid and sat. sodium bicarbonate solution, dried over magnesium sulfate and evaporated to give methyl 4-chloromethyl-2-nitrobenzoate (1.60 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:6])[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26]>ClCCl>[N+:25]([C:16]1[CH:17]=[N:18][C:19]2[C:24]([C:15]=1[NH:1][CH2:2][C:3]1([OH:6])[CH2:5][CH2:4]1)=[CH:23][CH:22]=[CH:21][CH:20]=2)([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: NCC1(O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2ccccc2c1NCC1(O)CC1
Temperature: 25 °C

Procedure:
To a 0° C. mixture of 1-(aminomethyl)cyclopropanol (approximately 36.7 mmol, prepared as described by Lysenko, I. L. and Kulinkovich, O. G. Russ. i J. Org Chem. 2001, 17, 1238-1243) and triethylamine (6.30 mL, 45.4 mmol) in dichloromethane (120 mL) was added a solution of 4-chloro-3-nitroquinoline (7.28 g, 34.9 mmol) in dichloromethane (30 mL). The suspension was stirred at room temperature over the weekend. The dichloromethane was removed under reduced pressure and the residue was suspended in water (150 mL) and stirred at room temperature for 3 hours. A solid was isolated by filtration and dried in a vacuum oven to afford 8.99 g of 1-{[(3-nitroquinolin-4-yl)amino]methyl}cyclopropanol as a yellow solid.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[OH-].[K+].[NH:12]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@@H:13]([C:24](ON1C(=O)CCC1=O)=[O:25])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O.O.CCOCC>[NH:12]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@@H:13]([C:24]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:25])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)ON1C(=O)CCC1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C[C@H](NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Yield: 74 %

Procedure:
Solutions of leucine (90.0 mmole.) in dimethylformamide (150 ml.) and potassium hydroxide (90.0 mmole.) in water (25 ml.) were combined and chilled in an ice-salt bath. A chilled mixture of BocDTrpOSu (89.7 mmole.) in dimethylformamide (100 ml.) was then added. The mixture was stirred for one hour at the ice-salt bath temperature, allowed to warm to room temperature overnight, and distributed between aqueous citric acid (5%) and ether. The aqueous layer was extracted twice more with ether. The ethereal extracts were combined and dried over magnesium sulfate. The product precipitated from the ether onto the drying agent. Ether was removed from the mixture. Extraction of the solids with methanol, removal of the methanol and recrystallization of the residue from methanol-water afforded BocDTrp-LeuOH in 74% yield (27.85 g., m.r. 187°-190° C.).
Reaction SMILES: [CH2:1]([Si:4]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Cl)=[CH:20][CH:19]=1.[Cl-].[NH4+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1C=CC=CC=1.O1CCCC1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:7]2[CH2:8][CH2:9][Si:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)([CH2:1][CH2:2][CH3:3])[CH2:5][CH:6]=2)=[CH:20][CH:19]=1
Reactant: Cl[Mg]c1ccc(Cl)cc1
Reactant: CCC[Si]1(c2ccccc2)CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CCC[Si]1(c2ccccc2)CC=C(c2ccc(Cl)cc2)CC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
10.0 g of 4-n-propyl-4-phenyl-4-silacyclohexanone was dripped into a 50 ml tetrahydrofuran solution of 1.0M p-chlorophenyl magnesium chloride at 40°-50° C. After stirring for 2 hours at 50° C., the mixture was poured into a saturated aqueous solution of ammonium chloride and extraction was conducted using benzene. 500 mg of p-toluenesulfonic acid monohydrate was then added to the benzene solution and refluxing was conducted while the water generated was distilled away. After the water stopped distilling away, the benzene layer was washed with an aqueous solution of sodium bicarbonate, dried and concentrated to obtain 4-(4-chlorophenyl)-1-phenyl-1-n-propyl-1-silacyclohex-3-ene. This was then dissolved in 50 ml of ethanol and hydrogenation was conducted using 1.0 g of palladium carbon as a catalyst. After the catalyst was filtered out, the product was concentrated to obtain 14.0 g of 4-(4-chlorophenyl)-1-phenyl-1-n-propyl-1-silacyclohexane.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:11]=2)[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:5]=1[CH2:25][CH3:26])(=O)[CH3:2].[B]>O1CCCC1>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[CH:8]=2)[C:4]([CH2:1][CH3:2])=[C:5]1[CH2:25][CH3:26]
Reactant: CCc1c(C(C)=O)c2ccc(C(=O)OC)cc2n1Cc1ccccc1Cl
Agent: [B]
Solvent: C1CCOC1
Product: CCc1c(CC)n(Cc2ccccc2Cl)c2cc(C(=O)OC)ccc12
Temperature: 20 °C
Reaction time: 1 h
Yield: 39.7 %

Procedure:
To a solution of methyl 3-acetyl-1-(2-chlorobenzyl)-2-ethylindole-6-carboxylate (110 mg) in tetrahydrofuran, (5 ml) was added 1M solution of boron in tetrahydrofuran (0.6 ml) in one portion at 0° C. The mixture was stirred at 20° C. for 1 hour, then quenched with water and extracted with ethyl acetate. The organic chase was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed or silica gel eluting with a mixture of hexane and ethyl acetate (2:1) to give methyl 1-(2-chlorobenzyl)-2,3-diethylindole-6-carboxylate (42 mg) as colorless crystals.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][O:8][CH2:9][C:10]([CH2:27][O:28][CH2:29][CH2:30][N:31]2C(=O)C3=CC=CC=C3C2=O)([CH2:12][O:13][CH2:14][CH2:15][N:16]2C(=O)C3=CC=CC=C3C2=O)[CH3:11])C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:31][CH2:30][CH2:29][O:28][CH2:27][C:10]([CH2:9][O:8][CH2:7][CH2:6][NH2:5])([CH2:12][O:13][CH2:14][CH2:15][NH2:16])[CH3:11]
Reactant: CC(COCCN1C(=O)c2ccccc2C1=O)(COCCN1C(=O)c2ccccc2C1=O)COCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(COCCN)(COCCN)COCCN
Temperature: 50 °C
Yield: 82.9 %

Procedure:
A solution of 1,1,1-tris(phthalimidoethoxymethyl)ethane (4.0 g, 6.30 mmol) in 100 mL of absolute ethanol was heated to 50C. Then a 55% solution of hydrazine hydrate (3.7 mL, 63.00 mmol) was added dropwise and the resulting mixture was heated at 50° C. for 5 hrs. The reaction was cooled to 25° C. and the solids were filtered. The filtrate was evaporated to give an oil which was purified over reversed phase packing (C-18) using a methanol/water gradient as eluant to yield 1,1,1-tris(aminoethoxymethyl)ethane (1.3 g, 5.22 mmol, 83 % ).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.[C:12](O)(=O)C.C=O>[Pd].O>[CH2:8]([O:7][C:5]([CH:4]1[CH2:3][CH2:2][N:1]([CH3:12])[CH2:11][CH2:10]1)=[O:6])[CH3:9]
Reactant: CC(=O)O
Reactant: CCOC(=O)C1CCNCC1
Agent: [Pd]
Agent: C=O
Solvent: O
Product: CCOC(=O)C1CCN(C)CC1
Temperature: 0 °C
Yield: 99.9 %

Procedure:
Ethyl isonipecotate (20) (5.00 g, 31.8 mmol) was dissolved in an ice-cold mixture of glacial acetic acid (3.80 g, 63.6 mmol) and water (11 mL). Then, a 37% aqueous formaldehyde solution (2.85 mL, 38.2 mmol) was added and the reaction mixture was hydrogenated over Pd/C (10%, 338 mg) at 58 psi H2 for 3.5 h at room temperature. The solid was removed by filtration through Celite, which was washed thoroughly with water (50 mL) and the filtrate was adjusted to pH 11 with 1 M NaOH under cooling. The resulting solution was extracted with Et2O (5×100 mL), the combined organic fractions were dried (MgSO4), and the solvent was removed under reduced pressure to provide 21 (5.44 g, quant.) as a colorless liquid that was used for the next step without further purification. 1H NMR (300 MHz, CDCl3): δ=1.25 (t, J=7.1 Hz, 3 H, OCH2CH3), 1.69-2.06 (m, 6 H, 2-Hax, 3-H2, 5-H2, 6-Hax), 2.18-2.32 (m, 1 H, 4-H), 2.27 (s, 3 H, NMe), 2.75-2.87 (m, 2 H, 2-Heq, 6-Heq), 4.13 (q, J=7.1 Hz, 2 H, OCH2CH3) ppm. —13C NMR (75.5 MHz, CDCl3): δ=14.1 (OCH2CH3), 28.2 (C-3, C-5), 40.5 (C-4), 46.3 (NMe), 54.9 (C-2, C-6), 60.2 (OCH2CH3), 175.0 (C═O) ppm. −MS (70 eV, EI): m/z (%)=171 (31) [M]+, 142 (59) [M-CH2CH3]+, 126 (40) [M-OCH2CH3]+, 98 (56) [M-CO2Et]+. —C9H17NO2 (171.24).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:31](Cl)=[O:32])[CH:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:42][CH2:41][NH:40][CH2:39][C:38]1=[O:43]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:31]([N:40]3[CH2:41][CH2:42][NH:37][C:38](=[O:43])[CH2:39]3)=[O:32])[C@H:13]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C1CNCCN1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)C1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazinone (Avocado Organics) to give the title compound. LC-MS: 607.2 [(M+H)+]
Reaction SMILES: [Na].[C:2]([CH2:4][C:5]([NH2:7])=[O:6])#[N:3].[Cl:8][C:9]1[CH:28]=[CH:27][C:12]([C:13]([C:15]2[C:24]([CH3:25])=[CH:23][C:18]([CH2:19][N:20]=[N+:21]=[N-:22])=[CH:17][C:16]=2[CH3:26])=[O:14])=[CH:11][CH:10]=1.C(O)(=O)C>C(O)C>[NH2:3][C:2]1[N:20]([CH2:19][C:18]2[CH:17]=[C:16]([CH3:26])[C:15]([C:13](=[O:14])[C:12]3[CH:27]=[CH:28][C:9]([Cl:8])=[CH:10][CH:11]=3)=[C:24]([CH3:25])[CH:23]=2)[N:21]=[N:22][C:4]=1[C:5]([NH2:7])=[O:6]
Reactant: Cc1cc(CN=[N+]=[N-])cc(C)c1C(=O)c1ccc(Cl)cc1
Reactant: N#CCC(N)=O
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(Cn2nnc(C(N)=O)c2N)cc(C)c1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 64.8 %

Procedure:
A stirred, 60° solution of sodium (105 mg, 4.55 mmol) in absolute ethanol (11.4 ml) was treated in one portion with 2-cyanoacetamide (382 mg, 4.55 mmol), kept 5 minutes, and treated in one portion with a solution of 4-(4-chlorobenzoyl)-3,5-dimethylbenzyl azide (1.05 g, 3.50 mmol) in absolute ethanol (4 ml). The mixture was refluxed 1 hour, cooled to ambient temperature, acidified with glacial acetic acid (577 μl, 605 mg, 9.10 mmol), and evaporated almost to dryness under vacuum. The residue was refluxed briefly with methanol (7 ml), cooled to ambient temperature, and filtered. The solid product was washed four times with small volumes of methanol, washed three times with water, and dried under vacuum at 40° C. to provide 870 mg (65%) 5-amino-1-(4-[4-chlorobenzoyl]-3,5-dimethylbenzyl)-1,2,3-triazole-4-carboxamide, m.p. 208°-209° C.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1.Cl[C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][N:12]([C:29]4[N:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[CH:14]1[CH2:15][CH2:16][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:18][CH2:19]1
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc2c(c1)CN(c1ncccn1)Cc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.1 %

Procedure:
A mixture of the amine from example 4 (200 mg, 0.53 mmol), 2-Chloropyrimidine (66 mg, 0.58 mmol) and potassium carbonate (72 mg, 0.53 mmol) in N,N-dimethylformamide (5 ml) was stirred at room temperature for 18 hours. TLC analysis showed starting materials remained, so additional 2-chloropyrimidine (66 mg, 0.58 mmol) was added, and the reaction was stirred at 80° C. for a further 72 hours. The cooled mixture was evaporated under reduced pressure, the residue was partitioned between ethyl acetate and brine, and the layers were separated. The organic layer was washed with water, wash with ammonium chloride solution, dried over magnesium sulphate and then evaporated under reduced pressure. The residual yellow oil was purified by column chromatography on silica gel using dichloromethane:methanol (95:5) as eluant, to afford the title compound as a yellow oil (117 mg).
Reaction SMILES: [C:1]([C:5](=[CH2:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]3[CH:19]=[N:20][CH:21]=[C:17]3[CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)([O:3]C)=[O:2].C[O-].[Na+].CO>O>[C:1]([C:5](=[CH2:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]3[CH:19]=[N:20][CH:21]=[C:17]3[CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)([OH:3])=[O:2]
Reactant: C=C(Cc1ccc(-c2cccc3cncn23)cc1)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=C(Cc1ccc(-c2cccc3cncn23)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 20 mg of 5-[p-(2-carbomethoxyprop-2-enyl)phenyl]imidazo[1,5-a]pyridine and 20 mg of sodium methoxide in 2 ml. of methanol is stirred under nitrogen for 1 hour at 25°. To the reaction mixture 2 ml. of water is added, and the homogenous solution is stirred at room temperature for 18 hours. The solvent is evaporated and the residue is redissolved in 5 ml of water and washed with 3 ml of ether. Acidification to pH=5, extraction with 10 ml of methylene chloride, drying over magnesium sulfate and evaporation yields 5-[p-(2-carboxyprop-2-enyl)phenyl]imidazo[1,5-a]pyridine, m.p. 171°-172°.
Reaction SMILES: [C:1](Cl)([CH3:3])=[O:2].Cl.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][N:17]([C:20]2[CH:21]=[CH:22][C:23]3[C:24]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29][C:25]=4[NH:26][C:27]=3[CH:28]=2)[C:16](=[O:34])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([N:31]1[CH2:32][CH2:33][C:24]2[C:23]3[CH:22]=[CH:21][C:20]([N:17]4[CH:18]=[CH:19][C:14]([O:13][CH2:6][C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=5)=[CH:15][C:16]4=[O:34])=[CH:28][C:27]=3[NH:26][C:25]=2[CH2:29][CH2:30]1)(=[O:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: O=c1cc(OCc2ccccc2)ccn1-c1ccc2c3c([nH]c2c1)CCNCC3
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2[nH]c3cc(-n4ccc(OCc5ccccc5)cc4=O)ccc3c2CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.8 %

Procedure:
AcCl (0.03 mL, 0.4 mmol) was added to a solution of 4-(benzyloxy)-1-(1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one hydrochloride (102 mg, 0.242 mmol), DMAP (6 mg, 0.05 mmol) and Et3N (0.10 mL, 0.73 mmol) in CH2Cl2 (10 mL) under N2, and the resulting solution was stirred at 25° C. for 4 h. The solution was concentrated under reduced pressure. Flash chromatography on silica gel (Et2O/(8:1.9:0.1 Et2O/MeOH/NH4OH) afforded 35 mg (34%) of the title compound as an off-white solid: mp 250-254° C.; 1H NMR (500 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.54 (d, J=7.5 Hz, 1H), 7.49-7.35 (m, 6H), 7.19 (dd, J=2.5, 2.5 Hz, 1H), 6.88-6.83 (m, 1H), 6.07 (dd, J=8.0, 2.5 Hz, 1H), 5.95 (d, J=2.5, 1H), 5.14 (s, 2H), 3.76-3.65 (m, 4H), 3.06-3.02 (m, 1H), 2.97-2.91 (m, 2H), 2.87-2.82 (m, 1H), 2.12 (s, 3H); ESI MS m/z 428 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>CO>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:16])=[O:2])=[CH:5][CH:6]=2)[CH:11]=1
Reactant: COC(=O)c1ccc(-c2cccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(-c2cccnc2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
Procedure J′: 648 mg of 4-Pyridin-3-yl-benzoic acid methyl ester (3.04 mmol) is dissolved in 15 ml of MeOH and 10 ml of 1N NaOH is added. The reaction mixture is stirred at 50° C. for 30 min and room temperature for overnight. MeOH is removed in vacuo and the residue is acidified to pH=4.0 by 1N HCl. Crystals are filtered and washed by water and dried to give 578 mg of 4-pyridin-3-yl-benzoic acid (96%). 1H-NMR(DMSO): 13.1(br,1H), 8.98(m, 1H), 8.64(m, 1H), 8.17(m, 1H), 8.07(d, 2H, J=8.0 Hz), 7.89(d, 2H, J=8.0 Hz), 7.57(m, 1H).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:17][C@H:18]([OH:30])[C:19]2[C:27]3[S:26][C:25](=[O:28])[NH:24][C:23]=3[C:22]([OH:29])=[CH:21][CH:20]=2)=[CH:11][CH:10]=1)(=O)=O.FC(F)(F)C(O)=O.[F:45][C:46]([F:61])([F:60])[C:47]([N:49]1[CH2:54][C:53]2([CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[O:52][CH2:51][CH2:50]1)=[O:48].C(N(CC)CC)C>CC#N>[OH:30][C@H:18]([C:19]1[C:27]2[S:26][C:25](=[O:28])[NH:24][C:23]=2[C:22]([OH:29])=[CH:21][CH:20]=1)[CH2:17][N:16]([CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:57]2[CH2:58][CH2:59][C:53]3([O:52][CH2:51][CH2:50][N:49]([C:47](=[O:48])[C:46]([F:45])([F:60])[F:61])[CH2:54]3)[CH2:55][CH2:56]2)=[CH:14][CH:13]=1)[C:31](=[O:32])[O:33][C:34]([CH3:37])([CH3:35])[CH3:36]
Reactant: O=C(N1CCOC2(CCNCC2)C1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(OCCOS(C)(=O)=O)cc1)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N(Cc1ccc(OCCN2CCC3(CC2)CN(C(=O)C(F)(F)F)CCO3)cc1)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Temperature: 60 °C
Reaction time: 25 h

Procedure:
A solution of (R)-2-(4-((tert-butoxycarbonyl(2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl)amino)methyl)phenoxy)ethyl methanesulfonate (example 108, step c) (2.20 g) in MeCN (8.5 mL) was added dropwise to a solution of 2,2,2-trifluoro-1-(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethanone trifluoroacetate (example 12, step d) (1.18 g) and triethylamine (0.81 mL) in MeCN (8.5 mL) at RT under argon. The resulting mixture was stirred at 60° C. under argon for 25 h. After cooling to RT the solvent was removed in vacuo. The brown residue was taken up in DCM (35 mL), washed with water (2×35 mL), dried over sodium sulphate, filtered and evaporated in vacuo. The yellow solid was purified by silica gel chromatography eluting with 0-10% MeOH/DCM to give the subtitle compound as a yellow solid. Yield 729 mg.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[N:15][C:14]([CH3:17])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[O:18]1[C:22]([C:23]2[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][N:24]=2)=[CH:21][N:20]=[CH:19]1>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[N:15][C:14]([CH3:17])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([C:22]3[O:18][CH:19]=[N:20][CH:21]=3)=[N:24][CH:25]=2)[CH2:2][CH2:3]1
Reactant: Cc1cnc(N2CCC(NC3CC3)CC2)cn1
Reactant: O=C(O)c1ccc(-c2cnco2)nc1
Product: Cc1cnc(N2CCC(N(C(=O)c3ccc(-c4cnco4)nc3)C3CC3)CC2)cn1

Procedure:
The title compound is prepared from cyclopropyl-[1-(5-methyl-pyrazin-2-yl)-piperidin-4-yl]-amine and 6-oxazol-5-yl-nicotinic acid following a procedure analogous to that described in Example 1. LC (method 7): tR=0.96 min; Mass spectrum (ESI+): m/z=405 [M+H]+.
Reaction SMILES: [N:1]1([CH2:10][CH2:11][OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.O[C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[N:1]1([CH2:10][CH2:11][O:12][C:14]2[CH:46]=[CH:45][C:17]([CH2:18][CH:19]3[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20]3=[O:44])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: OCCn1ccc2ccccc21
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: O=C1SC(Cc2ccc(OCCn3ccc4ccccc43)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 90.5 %

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 2.0 g of 2-(indol-1-yl)-ethanol (prepared as described in Preparation 13), 4.81 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 3.1 ml of tributylphosphine, 3.20 g of 1,1'-(azodicarbonyl)dipiperidine and 60 ml of anhydrous benzene were used, to give 5.69 g of the title compound, melting at 63.5°-65.9° C.