Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([C:5]#[CH:6])(C)C.C([Li])CCC.[CH3:12][C:13]1([CH3:25])[C:22]2[C:17](=[C:18]([CH:23]=[O:24])[CH:19]=[CH:20][CH:21]=2)[O:16][CH2:15][CH2:14]1.[Cl-].[NH4+]>C1COCC1>[C:5]([CH:23]([C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:17]=1[O:16][CH2:15][CH2:14][C:13]2([CH3:25])[CH3:12])[OH:24])#[CH:6]
Reactant: CC1(C)CCOc2c(C=O)cccc21
Reactant: C#C[Si](C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC(O)c1cccc2c1OCCC2(C)C
Yield: 132.1 %

Procedure:
7.6 ml (54.0 mmol) of trimethylsilylacetylene and 50 ml of THF are introduced into a three-necked flask. A solution of 22 ml (54.0 mmol) of n-butyllithium (2.5M in hexane) is added dropwise at -78° C. under a stream of nitrogen and the mixture is allowed to return to room temperature. The reaction mixture is introduced dropwise into a cold (-78° C.) solution composed of 9.30 g (49.0 mmol) of 4,4-dimethylchroman-8-carbaldehyde and of 50 ml of THF. The reaction mixture is allowed to return to room temperature, poured onto an aqueous ammonium chloride solution and extracted with ethyl ether and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. 14.00 g (100%) of the expected compound are obtained in the form of a yellow oil. 3.00 g (10.0 mmol) of this oil are mixed with 50 ml of THF, and 11.5 ml (12.6 mmol) of a tetrabutylammonium fluoride solution (1.1M in THF) are added dropwise. The reaction mixture is stirred at room temperature for one hour, is poured into water and extracted with ethyl ether and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. 2.30 g (100%) of the expected compound are collected in the form of a colourless oil.
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19]=[C:18]3[NH:26]C(=O)OC)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>C(O)C>[C:31]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19]=[C:18]3[NH2:26])[CH2:10][CH2:9]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COC(=O)Nc1nc2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: Cl
Solvent: CCO
Product: Nc1nc2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 12 parts of methyl [1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1H-benzimidazol-2-yl]carbamate, 60 parts of a concentrated hydrochloric acid solution and 80 parts of ethanol is stirred and refluxed overnight. The reaction mixture is evaporated and water is added to the residue. The free base is liberated in the conventional manner with ammonium hydroxide and extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from ethanol. The product is filtered off and dried, yielding 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1H-benzimidazol-2-amine; mp. 228.7° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[CH:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)([CH3:18])[CH3:17]>>[CH:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([S:33][CH3:34])=[CH:31][CH:32]=2)[C:13]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:15])=[CH:21][CH:20]=1)([CH3:18])[CH3:17]
Reactant: CSc1ccc(CNc2ccc(C(C)C)cc2)cc1
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Product: COc1ccc2c(c1)C(C(=O)N(Cc1ccc(SC)cc1)c1ccc(C(C)C)cc1)CCC2
Yield: 41.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.5 g) and (4-isopropylphenyl)[(4-methylthiophenyl)methyl]amine (2.0 g) as starting materials, N-(4-isopropylphenyl)-7-methoxy-N-[(4-methylthiophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.4 g) was obtained.
Reaction SMILES: CS([O:5][C:6]1[N:11]=[C:10]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:13](O)=[N:14][C:9]2=[CH:8][CH:7]=1)(=O)=O.P(Br)(Br)([Br:25])=O>>[Br:25][C:13]1[N:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C:10]2=[N:11][C:6]([OH:5])=[CH:7][CH:8]=[C:9]2[N:14]=1
Reactant: O=P(Br)(Br)Br
Reactant: Cc1ccccc1-n1c(O)nc2ccc(OS(C)(=O)=O)nc21
Product: Cc1ccccc1-n1c(Br)nc2ccc(O)nc21

Procedure:
From 2-hydroxy-3-o-tolyl-3H-imidazo[4,5-b]pyridin-5-yl methanesulfonate and phosphoryl tribromide, prepared in a similar manner as the one described in Example 1.136, the title compound was obtained. LCMS m/z=304.20 [M+H]+, 1H NMR (400 MHz, methanol-d4) δ ppm 2.05 (s, 3H), 6.7 (d, J=8.6 Hz, 1H), 7.33 (d, J=7.8, 1H), 7.42-7.47 (m, 1H), 7.48-7.53 (m, 2H), 7.94 (d, J=8.7, 1H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[C:14]([CH3:16])([CH3:15])[CH2:13][NH:12][C:11]1=[O:17])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][N:10]1[C:14]([CH3:15])([CH3:16])[CH2:13][NH:12][C:11]1=[O:17]
Reactant: CC(C)(C)OC(=O)NCCN1C(=O)NCC1(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CNC(=O)N1CCN
Reaction time: 16 h
Yield: 93 %

Procedure:
[2-(5,5-Dimethyl-2-oxo-imidazolidin-1-yl)-ethyl]-carbamic acid tert-butyl ester (450 mg, 1.75 mmol) was dissolved in DCM (5 mL) and TFA (1 mL) was added. The mixture was allowed to stand for 16 h, concentrated, and purified by SCX ion exchange chromatography to give the product as a yellow oil (256 mg, 93%).
Reaction SMILES: [CH3:1][C@:2]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:11]2[C:6]3=[C:7]([C@:15]([CH3:24])([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:16][CH2:17][N:5]3[CH2:4][CH2:3]1)[CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=2.C(N(CC)CC)C.Cl[C:39]([O:41][CH3:42])=[O:40]>ClCCl>[CH3:1][C@:2]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:11]2[C:6]3=[C:7]([C@:15]([CH3:24])([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:16][CH2:17][N:5]3[CH2:4][CH2:3]1)[CH:8]=[C:9]([NH:12][C:39](=[O:40])[O:41][CH3:42])[CH:10]=2
Reactant: C[C@@]1(c2ccccc2)CCN2CC[C@@](C)(c3ccccc3)c3cc([N+](=O)[O-])cc1c32
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Nc1cc2c3c(c1)[C@](C)(c1ccccc1)CCN3CC[C@@]2(C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution (1S,7S)-1,7-dimethyl-9-nitro-1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinoline (7), (115 mg, 0.31 mmol), in dichloromethane (15 mL) was added three equivalent of triethyl amine (0.129 mL, 0.93 mmol), followed by methyl chloroformate (0.031 mL, 0.406 mmol) under argon at 0° C. The reaction mixture was then stirred at room temperature for overnight. The mixture was quenched with water (30 mL). The residue was isolated in a typical aqueous workup and purified by MPLC (medium pressure liquid chromatography) using silica gel column with 10 to 15% EtOAc:Hexane to give methyl (1S,7S)-1,7-dimethyl-1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-ylcarbamate (829), (69 mg 52%). 1H NMR (300 MHz, Acetone-d6) ppm 1.72 (s, 6H) 1.89-2.03 (m, 2H) 2.17-2.30 (m, 2H) 2.73-2.88 (m, 2H) 2.92-3.03 (m, 2H) 3.56 (s, 3H) 7.05-7.33 (m, 12H) 8.02 (br. s., 1H).
Reaction SMILES: [C:1]([C:4]1[C:13]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)(=[O:3])[CH3:2].[CH3:25][Mg]Cl.[NH4+].[Cl-].Cl>C1COCC1>[OH:3][C:1]([C:4]1[C:13]([O:14][S:15]([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)(=[O:17])=[O:16])=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)([CH3:25])[CH3:2]
Reactant: CC(=O)c1nc2ccccc2cc1OS(=O)(=O)c1ccc(C)cc1
Reactant: C[Mg]Cl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)Oc2cc3ccccc3nc2C(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Toluene-4-sulfonic acid 2-acetyl-quinolin-3-yl ester (3.58 g, 10.5 mmol) in 40 mL of THF was cooled to around −20 to −25° C. Methyl magnesium chloride (5.25 mL of 3M solution in THF) was added dropwise over a period of 10 minutes. The reaction mixture was allowed to stir 18 hours at ambient temperature, and then was poured into saturated aqueous NH4Cl and acidified with 1N HCl to pH 5. The resulting mixture was extracted with ethyl acetate and the combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated to dryness under reduced pressure to give 3.75 g of toluene-4-sulfonic acid 2-(1-hydroxy-1-methyl-ethyl)-quinolin-3-yl ester as an oil that solidified on standing.
Reaction SMILES: ClC[SiH2][C:4]1[CH2:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.C1C[O:16][CH2:15][CH2:14]1>>[CH2:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[C:4]1[CH2:14][CH2:15][OH:16]
Reactant: ClC[SiH2]C1=Cc2ccccc2C1
Reactant: C1CCOC1
Product: OCCC1=Cc2ccccc2C1
Temperature: -78 °C
Reaction time: 15 h
Yield: 33.4 %

Procedure:
Under nitrogen flow, a 1 L three-necked flask receives 400 mL of THF and 8 g of 2-chloromethylsilylindene and the mixture is cooled to −78° C. To this, 38.5 mL (38.5 mmol) of a solution (1.0M) of LiN(trimethylsilylene)2 in THF is added dropwise. After stirring at room temperature for 15 hours, the solvent is distilled off and the residue is extracted with 300 mL of hexane. The solvent was distilled off to obtain 2.2 g (6.4 mmol) of (1,2′-dimethylsilylene)(2,1′-dimethylsilylene) (indene) 2 (yield:33.4%). The results of 1H-NMR analysis (90 MHz, CDCl3) are as follows: δ-0.69, 0.73 (12H, dimethylsilylene), 3.66 (4H, —CH2—), 7.17 (8H, Ar—H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH:9]1[CH:13]=[CH:12][CH:11]=[N:10]1>O1CCCC1>[N:9]1([C:4]2[N:5]=[C:6]([N:9]3[CH:13]=[CH:12][CH:11]=[N:10]3)[CH:7]=[CH:2][N:3]=2)[CH:13]=[CH:12][CH:11]=[N:10]1
Reactant: c1cn[nH]c1
Reactant: Clc1cc(Cl)ncn1
Solvent: C1CCOC1
Product: c1cnn(-c2ccnc(-n3cccn3)n2)c1
Yield: 84.4 %

Procedure:
In anhydrous tetrahydrofuran, 149 mg of 4,6-dichloropyrimidine was substituted with 136 mg of pyrazole. The reaction mixture was treated according to the procedure of Example 1 to yield 179 mg of 2,4-bis(1-pyrazolyl)pyrimidine, recrystallized from n-hexane, the compound had a melting point of 152°-153° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14](#[N:17])[CH:15]=[CH2:16]>CO>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH2:16][CH2:15][C:14]#[N:17])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC#N
Reactant: NC1CCN(Cc2ccccc2)C1
Solvent: CO
Product: N#CCCNC1CCN(Cc2ccccc2)C1
Temperature: 70 °C
Yield: 88.5 %

Procedure:
4.00 g (22.7 mmol) of 1-benzyl-3-aminopyrrolidine was dissolved in 70 ml of methanol, 1.49 ml (22.7 mmol) of acrylonitrile was added thereto, and the mixture was heated to 70° C. After completion of the reaction, the reaction solution was evaporated, and the resulting crude product was subjected to 100 g of Cromatorex NH silica gel (ethyl acetate 100%), to give 4.60 g (20.1 mmol, 88.4%) of the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15]I)[N:14]=1)=[O:8].[Na].[CH3:21][C:22]1[C:23]([OH:28])=[N:24][CH:25]=[CH:26][N:27]=1.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][O:28][C:23]2[C:22]([CH3:21])=[N:27][CH:26]=[CH:25][N:24]=2)[N:14]=1)=[O:8]
Reactant: Cc1nccnc1O
Reactant: O=C(NCc1cccc(F)c1)Nc1nc(CI)cs1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nccnc1OCc1csc(NC(=O)NCc2cccc(F)c2)n1
Reaction time: 8 h

Procedure:
1-(3-fluorobenzyl)-3-(4-(iodomethyl)thiazol-2-yl)urea (1.0 mmol) and excess of 3-methylpyrazin-2-ol sodium salt were dissolved in N,N-dimethylformamide (3 ml). The mixture was stirred overnight. Water (20 ml) was added and the product was extracted three times with dichloromethane. The organic was dried over Na2SO4, filtered, and concentrated. The crude was purified by column chromatography using 0-70% gradient of saturated ammonia/MeOH and dichloromethane. 1H NMR (400 MHz, DMSO-d6): 10.73 (s, 1H), 7.48 (d, 1H), 7.36 (m, 1H), 7.15 (d, 1H), 7.06-7.12 (m, 3H), 6.96)m, 1H), 6.89 (s, 1H), 4.99 (s, 2H), 4.33 (d, 2H), 2.28 (s, 3H). MS (ES+): M/Z 374 (M+1).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]([O:9]CC)=[O:8])=[N+:2]=[N-:3].[OH-].[K+]>CO.O>[N:1]([CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[N+:2]=[N-:3]
Reactant: CCOC(=O)CCCN=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: [N-]=[N+]=NCCCC(=O)O
Reaction time: 11 h
Yield: 92.4 %

Procedure:
Ethyl 4-bromobutanoate (17.11 g, 87.7 mmol) and NaN3 (28.50 g, 438.5 mmol) was dissolved in 70 mL DMF and reacted at 77° C. for 30 hours. 250 mL of 4:1 EtOAc/hexanes was added, and was washed twice with 250 mL saturated aqueous sodium bicarbonate, and once with 200 mL water. Organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give ethyl 4-azidobutanoate 6 (13.26 g, 96%). Ethyl 4-azidobutanoate 6 (6.18 g, 39.29 mmol) was then saponified using excess KOH in 12:10 methanol/water at 0° C. for 5 minutes and then ambient temperature for 11 hours, followed by acid workup to yield 4-Azidobutanoic acid 7 (4.69 g, 92%). 1H NMR (400 MHz, cdcl3) δ 1.71-1.98 (2H, m), 2.45 (2H, t, J=7.2 Hz), 3.35 (2H, t, J=6.7 Hz), 11.21 (1H, s) ppm.
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.[NH2:25][CH2:26][CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1.[C:37]([NH:40][CH2:41][C:42](O)=[O:43])(=[O:39])[CH3:38]>CN(C=O)C>[C:37]([NH:40][CH2:41][C:42]([NH:25][CH2:26][CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)=[O:43])(=[O:39])[CH3:38]
Reactant: CC(=O)NCC(=O)O
Reactant: NCCc1c[nH]c2ccccc12
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)NCC(=O)NCCc1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 12 h
Yield: 77.8 %

Procedure:
Diphenylphosphorylazide (5.8 ml, 27.5 ml) and triethylamine (3.85 ml, 27.5 ml) were added in succession to a mixture of tryptamine (4.32 g, 27 mmol) and N-acetylglycine (3.3 g, 28 mmol) in DMF (100 ml) cooled to 0° C. The mixture was stirred under nitrogen at ambient temperature for 12 h, then the solvent was eliminated under reduced pressure. The residue obtained was flash chromatographed on silica gel to produce the expected product (m=5.5 g, 21 mmol), giving a yield of 78%.
Reaction SMILES: [CH2:1]([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[C:11]([O:13][C:14](=[O:15])[CH:5]21)=[O:12])[CH:2]=[CH2:3].[CH2:16]([CH:18]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:19][NH2:20])[CH3:17]>>[CH2:16]([CH:18]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:19][N:20]=[C:14]([CH:5]1[CH:6]([C:11]([OH:13])=[O:12])[CH:7]2[CH2:10][C:4]1([CH2:1][CH:2]=[CH2:3])[CH:9]=[CH:8]2)[OH:15])[CH3:17]
Reactant: CCCCC(CC)CN
Reactant: C=CCC12C=CC(C1)C1C(=O)OC(=O)C12
Product: C=CCC12C=CC(C1)C(C(=O)O)C2C(O)=NCC(CC)CCCC

Procedure:
The procedure described in Example 3 is repeated, except that 204 g of allyl-bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid anhydride and 129 g of 2-ethylhexylamine are used. 17 g of water are split off ayt 115° to 160° C. under 4,000 Pa in the course of 4.5 hours. 292.05 g (92.6% of theory) of a fraction of boiling point 160°-164° C. under 10.7 Pa, nD20 1.5038 and η25 0.68 Pa.s are obtained.
Reaction SMILES: [O:1]=[C:2]([CH3:20])[CH2:3][CH2:4][C:5]1[CH:19]=[CH:18][C:8]([O:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[O:1]=[C:2]([CH3:20])[CH2:3][CH2:4][C:5]1[CH:19]=[CH:18][C:8]([O:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1
Reactant: CCOC(=O)CCCOc1ccc(CCC(C)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(=O)CCc1ccc(OCCCC(=O)O)cc1
Yield: 59.9 %

Procedure:
4-[4-(3-Oxobutyl)phenoxy]butanoic acid, ethyl ester (716 mg, 2.57 mmol) is dissolved in 5 mL of methanol/water (3:2) and treated with 1.24 g (9.0 mmol) of potassium carbonate according to the procedure described for Example 4 to give 385 mg (60%) of 4-[4-(3-oxobutyl)phenoxy]butanoic acid as a white powder: m.p. 97°-99°; the 1H NMR (300 MHz, CDCl3) is consistent with the desired product; IR (neat) 1730, 1700, 1620, 1520 cm-1 ; Analysis calcld for C14H18O4 : C, 67.18; H, 7.25; found: C, 66.55; H, 7.09.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([NH:20][C:21]3[C:30]4[C:25](=[C:26]([C:31](=[O:33])[NH2:32])[CH:27]=[CH:28][CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH3:19])[CH:13]=2)=[N:8][CH:7]=1)=[O:5])C.[OH-].[Na+]>>[C:31]([C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:25]=1[N:24]=[CH:23][N:22]=[C:21]2[NH:20][CH:18]([C:14]1[CH:13]=[C:12]([NH:11][C:9]2[O:10][C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]=2)[CH:17]=[CH:16][CH:15]=1)[CH3:19])(=[O:33])[NH2:32]
Reactant: CCOC(=O)c1cnc(Nc2cccc(C(C)Nc3ncnc4c(C(N)=O)cccc34)c2)o1
Agent: [Na+]
Agent: [OH-]
Product: CC(Nc1ncnc2c(C(N)=O)cccc12)c1cccc(Nc2ncc(C(=O)O)o2)c1

Procedure:
The ester was hydrolyzed with 1N NaOH at 60° C. for 2 h to get the title compound. LCMS (M+1) 419.
Reaction SMILES: [CH:1]1[C:2]2[N:3]([CH:12]=[CH:13][CH:14]=2)[CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)Cl>[Br:15][C:12]1[N:3]2[CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=[CH:1][C:2]2=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1cn2cccc2cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCOC(=O)c1cn2c(Br)ccc2cn1
Reaction time: 1 h
Yield: 57 %

Procedure:
To a solution of ethyl pyrrolo[1,2-a]pyrazine-3-carboxylate (0.60 g, 3.18 mmol) in CH2Cl2 (60 mL) is added N-bromosuccinimide (0.56 g, 3.18 mmol) in one portion. After 1 h, solvent is removed in vacuo and the crude solid purified using preparative HPLC (1% IPA/heptane (0-5 minutes) to 2% isocratic) to give a brown solid for ethyl 6-bromopyrrolo[1,2-a]pyrazine-3-carboxylate. Yield 57%. MS (ESI+) for C10H9BrN2O2 m/z 271.01 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH2:4][C@H:3]1[O:18][CH3:19].[Cl:20][C:21]1[C:22]([O:33][CH3:34])=[C:23]([C:27]([OH:32])=[C:28]([CH2:30][CH3:31])[CH:29]=1)[C:24](Cl)=[O:25].C(N(CC)CC)C>ClC(Cl)Cl>[Cl:20][C:21]1[C:22]([O:33][CH3:34])=[C:23]([C:27]([OH:32])=[C:28]([CH2:30][CH3:31])[CH:29]=1)[C:24]([NH:1][C@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11](=[O:12])[N:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:4][C@H:3]1[O:18][CH3:19])=[O:25]
Reactant: CO[C@@H]1CN(CCCC(=O)N2CCCC2)CC[C@@H]1N
Reactant: CCc1cc(Cl)c(OC)c(C(=O)Cl)c1O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCc1cc(Cl)c(OC)c(C(=O)N[C@H]2CCN(CCCC(=O)N3CCCC3)C[C@H]2OC)c1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.9 %

Procedure:
To a stirred solution of 4.04 parts of cis-1-[4-(4-amino-3-methoxy-1-piperidinyl)-1-oxobutyl]pyrrolidine in 225 parts of trichloromethane was added a solution of 4.15 parts of 3-chloro-5-ethyl-6-hydroxy-2-methoxybenzoyl chloride in trichloromethane. After stirring for 15 minutes at room temperature, 1.9 parts of N,N-diethylethanamine were added and the whole was stirred overnight at room temperature. The reaction mixture was washed with water, saturated with ammonia and twice with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 5.2 parts (71.9%) of cis-3-chloro-5-ethyl-6-hydroxy-2-methoxy-N-[3-methoxy-1-[4-oxo-4-(1-pyrrolidinyl)butyl]-4-piperidinyl]benzamide; mp. 90.8° C. (compound 67).
Reaction SMILES: Cl.[CH3:2][CH:3]([O:5][C:6]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]4[CH2:28][NH:27][CH2:26][CH2:25][CH2:24][C:23]=4[CH:29]=3)[N:15]=2)=[CH:10][C:7]=1[C:8]#[N:9])[CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41].CCOC(C)=O>CN(C=O)C>[C:8]([C:7]1[CH:10]=[C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]4[CH2:28][N:27]([CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:26][CH2:25][CH2:24][C:23]=4[CH:29]=3)[N:15]=2)[CH:12]=[CH:13][C:6]=1[O:5][CH:3]([CH3:2])[CH3:4])#[N:9]
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCCNC4)no2)cc1C#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCN1CCCc2cc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)ccc2C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 108.4 %

Procedure:
2-[(1-Methylethyl)oxy]-5-[3-(2,3,4,5-tetrahydro-1H-2-benzazepin-7-yl)-1,2,4-oxadiazol-5-yl]benzonitrile hydrochloride (Example 3) (70 mg, 0.170 mmol) and caesium carbonate (167 mg, 0.511 mmol) in dry DMF (5 ml) were treated with ethyl 4-bromobutyrate (0.037 ml, 0.256 mmol) and stirred at 60° C. for 2 hours. Additional quantities of ethyl 4-bromobutyrate (37 ul) were added and the reaction heated at 60° C. for 3 hours. The reaction was left standing overnight. EtOAc (50 ml) was added and the mixture washed with water (2×60 ml), dried over anhydrous MgSO4 and evaporated to yield the title compound (90 mg) as a clear, colourless oil. MS (ES) C28H32N4O4 requires 488; found 489.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26]([OH:28])=O)[CH2:11]2)=[O:9])[CH2:4][C:3]1=[O:29].Cl.O[N:32]=[C:33]([NH2:36])[CH2:34][CH3:35]>>[CH2:34]([C:33]1[N:36]=[C:26]([CH:12]2[CH2:13][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:20][CH:21]=3)[CH2:15][N:10]([C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[C:3](=[O:29])[CH2:4]3)=[O:9])[CH2:11]2)[O:28][N:32]=1)[CH3:35]
Reactant: CCC(N)=NO
Reactant: CN1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1=O
Agent: Cl
Product: CCc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCN(C)C(=O)C3)C2)n1

Procedure:
250 mg (0.605 mmol) of 1-[(4-methyl-3-oxopiperazin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 209A) and 82.9 mg (0.665 mmol) of N′-hydroxypropanimidamide hydrochloride were reacted according to the General Method 1. Yield: 110 mg (39% of theory).
Reaction SMILES: [C:1]([N:5]1[CH:9]2[CH2:10][CH2:11][CH:6]1[CH:7]([C:12]1[CH:13]=[CH:14][C:15](Cl)=[N:16][CH:17]=1)[CH2:8]2)([O:3][CH3:4])=[O:2].[H][H]>CO>[C:1]([N:5]1[CH:6]2[CH2:11][CH2:10][CH:9]1[CH2:8][CH:7]2[C:12]1[CH:17]=[N:16][CH:15]=[CH:14][CH:13]=1)([O:3][CH3:4])=[O:2]
Reactant: [H][H]
Reactant: COC(=O)N1C2CCC1C(c1ccc(Cl)nc1)C2
Solvent: CO
Product: COC(=O)N1C2CCC1C(c1cccnc1)C2
Yield: 71.8 %

Procedure:
N-carbomethoxy-5-(2-chloro-5-pyridyl)-7-aza-bicyclo[2.2.1]hept-2-ene 25 (16 mg) was dissolved in 3 ml methanol containing 7 mg 10% palladium on carbon. The mixture was hydrogenated under a slightly elevated pressure of hydrogen for one hour. After removal of catalyst and solvent, the residue was partitioned between ether and aqueous sodium bicarbonate. The aqueous layer was extracted with ether and the combined organic layer was dried over magnesium sulfate. Removal of solvent gave 10 mg of 7-carbomethoxy-2-(3-pyridyl)-7-azanorbornane (12). MS (CI) m/z 233 (M+1), H1-NMR 3.72, 3.66 (2s, N-COOCH3).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C(O)C>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:4]1[N:3]=[C:2]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=1
Reactant: Clc1cc(-c2ccccn2)nc(-c2ccccn2)n1
Reactant: C1CNCCN1
Solvent: CCO
Product: c1ccc(-c2cc(N3CCNCC3)nc(-c3ccccn3)n2)nc1

Procedure:
4-Chloro-2,6-bis(2-pyridinyl)pyrimidine [prepared by the method of J.A.C.S. 32, 1591 (1967), 4.2 g] piperazine (13.44 g) and ethanol (70 ml) are heated at reflux for 2 hr. The mixture is allowed to cool and the solvent is removed under reduced pressure. The residue is dissolved in chloroform (250 ml), washed with water (twice), dried over sodium sulfate and concentrated under reduced pressure to give an oil. The oil is crystallized from ether to give the title compound, m.p. 159°-161°; MS (m/e) 318 (M+)