Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:19][CH2:20][C:21](Cl)=[O:22]>ClCCl>[CH2:5]([N:4]([CH:1]([CH3:3])[CH3:2])[C:21](=[O:22])[CH2:20][Cl:19])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)NCc1ccccc1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N(Cc1ccccc1)C(=O)CCl
Yield: 101.4 %

Procedure:
To a solution of 5.00 g of N-isopropylbenzylamine and 3.74 g of triethylamine in 60 ml of dry dichloromethane was added dropwise 3.84 g of chloroacetyl chloride with stirring under ice-cooling. The mixture was heated under reflux for 2 hours. After cooling, the reaction mixture was successively washed with water, a 10% hydrochloric acid and an aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 7.67 g of N-benzyl-2-chloro-N-isopropylacetamide in an oil.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3](=[O:11])[CH2:4]P(=O)(OC)OC.[H-].[Na+].[Br:15][C:16]1[CH:17]=[CH:18][C:19]2[O:23][CH2:22][C:21](=O)[C:20]=2[CH:25]=1.O>C1COCC1>[Br:15][C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22]([CH2:4][C:3]([N:2]([CH3:1])[CH3:12])=[O:11])=[CH:21][C:20]=2[CH:25]=1
Reactant: O=C1COc2ccc(Br)cc21
Reactant: COP(=O)(CC(=O)N(C)C)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)Cc1cc2cc(Br)ccc2o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dimethyl [2-(dimethylamino)-2-oxoethyl]phosphonate (5 g) was added to a stirred suspension of sodium hydride (1.02 g of a 60% dispersion in oil) in dry THF (100 ml) at 0° under nitrogen. After stirring for 15 minutes 5-bromo-3-(2H)-benzofuranone (5.0 g) in THF (20 ml) was added dropwise and stirred at room temperature for 3 h. Water (50 ml) was added and the mixture extracted with ethyl acetate (3×50 ml), dried and the solvent removed in vacuo. The crude material was purified by flash chromatography using 50% ethyl acetate/hexane as eluant to yield the title compound as a pale yellow solid m.p. 92°-94° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.[CH3:6][C:7]1[C:12](=[O:13])[C:11]2[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([O-:20])=[O:19])[C:10]=2[O:9][C:8]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Na+]>CN(C)C=O.O>[Br:1][CH2:2][CH2:3][CH2:4][O:20][C:18]([C:17]1[C:10]2[O:9][C:8]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[C:7]([CH3:6])[C:12](=[O:13])[C:11]=2[CH:14]=[CH:15][CH:16]=1)=[O:19]
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)[O-])cccc2c1=O
Reactant: BrCCCBr
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccc2)oc2c(C(=O)OCCCBr)cccc2c1=O
Temperature: 25 °C
Reaction time: 120 h
Yield: 69.6 %

Procedure:
30 g of 1,3-dibromopropane was added dropwise at ambient temperature to a suspension of 30 g of sodium 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylate in 150 ml of dimethylformamide and 35 ml of water. The reaction mixture was stirred at ambient temperature for 5 days. 100 ml of water was added and stirring was continued for a further 15 minutes. The precipitate was filtered off by suction, washed with water and purified by flash chromatography on silica gel, eluting with chloroform:ethyl acetate 95:5. The collected fractions were evaporated to dryness in vacuo and the residue was recrystallized from ethanol to give 27.7 g of the title compound, m.p. 114°-115° C.
Reaction SMILES: C(OC(=O)NC1CC2C(=CC=C(NC(C3C(C4C=CC(C(F)(F)F)=CC=4)=CC=CC=3)=O)C=2)C1)(C)(C)C.C1(S([NH:46][CH:47]2[CH2:55][C:54]3[C:49](=[CH:50][CH:51]=[C:52]([NH:56][C:57]([C:59]4C(C5C=CC(C(F)(F)F)=CC=5)=CC=CC=4)=[O:58])[CH:53]=3)[CH2:48]2)(=O)=O)C=CC=CC=1.NC1C=C2C(=CC=1)CC(NC(=O)C)C2.[Br:89][C:90]1[CH:98]=[CH:97][CH:96]=[CH:95][C:91]=1[C:92](Cl)=[O:93]>>[C:57]([NH:56][CH:52]1[CH2:53][C:54]2[C:50](=[CH:49][CH:48]=[C:47]([NH:46][C:92](=[O:93])[C:91]3[CH:95]=[CH:96][CH:97]=[CH:98][C:90]=3[Br:89])[CH:55]=2)[CH2:51]1)(=[O:58])[CH3:59]
Reactant: O=C(Cl)c1ccccc1Br
Reactant: O=C(Nc1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)C2)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: CC(=O)NC1Cc2ccc(N)cc2C1
Agent: CC(C)(C)OC(=O)NC1Cc2ccc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)cc2C1
Product: CC(=O)NC1Cc2ccc(NC(=O)c3ccccc3Br)cc2C1

Procedure:
The title compound is prepared as described for {5-[(4′-trifluoromethylbiphenyl-2-carbonyl)-amino]-indan-2-yl}-carbamic acid tert-butyl ester (the title E compound of Example 1) using N-(5-amino-indan-2-yl)-acetamide (the title A compound; 1.05 g, 5.50 mmol) and 2-bromo-benzoyl chloride (the title B compound; 1.21 g, 5.50 mmol) to give the product, mp 216-217° C. MS (ES+), m/z 373 (M+H), 375 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=3)[O:15][CH:10]2[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)[CH3:2].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:34][CH2:35][OH:36])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]>ClCCl.B(F)(F)F.CCOCC>[OH:15][CH:10]([C:9]([O:36][CH2:35][CH2:34][C:28]1[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[CH:27]=1)([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=1)[C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: CCc1ccc(C2(c3ccc(CC)cc3)OC2C(=O)OC)cc1
Reactant: COc1ccc(CCO)cc1OC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCc1ccc(C(OCCc2ccc(OC)c(OC)c2)(c2ccc(CC)cc2)C(O)C(=O)OC)cc1
Reaction time: 1.5 h

Procedure:
6 g (19.3 mmol) of methyl 3,3-di(4-ethylphenyl)-2,3-epoxypropionate (crude) and 3.52 g (19.3 mmol) of 2-(3,4-dimethoxyphenyl)ethanol were dissolved in 20 ml of dichloromethane and, at room temperature, 5 drops of boron trifluoride etherate were added. The solution was stirred for 1.5 hours. The solvent was then distilled off, and the residue, a pale yellow oil (8.66 g, 91%), was immediately reacted further.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][NH:19][C:20]2[N:30]=[CH:29][CH:28]=[CH:27][C:21]=2[C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH2:12][CH2:11]1.[Cl:31]N1C(=O)CCC1=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:31][C:28]1[CH:29]=[N:30][C:20]([NH:19][CH2:18][CH2:17][CH2:16][N:13]2[CH2:12][CH2:11][N:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[O:3][CH3:2])[CH2:15][CH2:14]2)=[C:21]([CH:27]=1)[C:22]([N:24]([CH3:26])[CH3:25])=[O:23]
Reactant: COc1ccccc1N1CCN(CCCNc2ncccc2C(=O)N(C)C)CC1
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1N1CCN(CCCNc2ncc(Cl)cc2C(=O)N(C)C)CC1
Temperature: 55 °C
Reaction time: 4 h
Yield: 65.9 %

Procedure:
A mixture of 2-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propylamino}-N,N-dimethylnicotinamide hydrochloride (0.287 g, 0.66 mmol), prepared as in Example 21, in 6 mL of DMF was heated to 50° C. and N-chlorosuccinimide (0.1 g, 0.73 mmol) was added. The mixture was stirred at 55° C. for 4 hours, diluted with water and basified with K2CO3 giving a precipitate. The precipitate was extracted with diethyl ether and the ether layer was washed twice with brine, dried (MgSO4) and concentrated. The residue was purified on silica gel by column chromatography eluting with 5% methanol/methylene chloride to give 5-chloro-2-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propylamino}-N,N-dimethylnicotinamide (0.188 g, 0.435 mmol) as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH:9]1([CH2:12][NH2:13])[CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>O>[Cl:8][C:4]1[N:3]=[C:2]([NH:13][CH2:12][CH:9]2[CH2:11][CH2:10]2)[CH:7]=[N:6][CH:5]=1
Reactant: NCC1CC1
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Clc1cncc(NCC2CC2)n1
Temperature: 80 °C
Reaction time: 23 h

Procedure:
A mixture of 2,6-dichloropyrazine (2.99 g), 1-cyclopropylmethanamine (2.14 g), potassium carbonate (4.14 g) and DMA (20 mL) was stirred at 80° C. for 23 hr. Water (15 mL) was added, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. This was used without purification for the next reaction.
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=1.C(N1C=CN=C1)([N:15]1C=CN=C1)=O.C([N-]C(C)C)(C)C>C1COCC1.CN(C=O)C>[C:1]([NH2:15])(=[O:12])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=1
Reactant: O=C(O)c1cccc(C(=O)O)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CC(C)[N-]C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(C(=O)O)c1
Temperature: 20 °C
Reaction time: 13.5 h
Yield: 80 %

Procedure:
These compounds are preferably prepared as set forth as follows. An ester, preferably the monomethyl ester of isophthalic acid or methyl 5-methyl-1,3-isophthalate is dissolved in a THF/DMF mixture. 1,1′-Carbonyldiimidazole is added at 20-25 degrees C. The diisopropyl amide is added. After 3-24 hr of stirring at 20 degrees C. to the reflux temperature of the solvent, the reaction mixture is partitioned between saturated aqueous ammonium chloride and a water immiscible organic solvent such as ethyl acetate. The aqueous layer is separated and extracted twice more with the organic solvent (ethyl acetate). The solvent removed and the residue thus obtained is basified to yield the isophthalic amide (IIa) in 80% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][OH:18])[C:10]=1[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([O:28][C:29]([NH:31][CH2:32][C:33](=[O:39])[CH2:34][CH2:35][C:36](O)=[O:37])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:21]([O:28][C:29]([NH:31][CH2:32][C:33](=[O:39])[CH2:34][CH2:35][C:36]([O:18][CH2:17][CH2:16][N:11]1[CH:12]=[CH:13][C:14](=[O:15])[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]1[CH2:19][CH3:20])=[O:37])=[O:30])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCc1c(OCc2ccccc2)c(=O)ccn1CCO
Reactant: O=C(O)CCC(=O)CNC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCc1c(OCc2ccccc2)c(=O)ccn1CCOC(=O)CCC(=O)CNC(=O)OCc1ccccc1
Reaction time: 24 h
Yield: 86.7 %

Procedure:
4-(Dimethylamino)pyridine (3.3 mg, 0.0274 mmol) was added to a stirred solution of 3-(benzyloxy)-2-ethyl-1-(2-hydroxyethyl)pyridin-4(1H)-one (6) (149 mg, 0.547 mmol), 5-(benzyloxycarbonylamino)-4-oxopentanoic acid (5) (145 mg, 0.547 mmol) and N,N′-dicyclohexylcarbodiimide (118 mg, 0.574 mmol) in dichloromethane (8 mL). After 24 h, the resulting suspension was filtered through cotton wool, eluting with dichloromethane. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on silica gel, eluting with ethyl acetate then methanol, to give the title compound 7 (247 mg, 87%) as a colourless oil, RF 0.7 (MeOH); δH (300 MHz; CDCl3) 7.46-7.20 (11H, m, Ar and Pyr 6-H), 6.40 (1H, d, J 9.0 Hz, Pyr 5-H), 5.97 (1H, br s, NH), 5.22 (2H, s, PhCH2), 5.09 (2H, s, PhCH2), 4.22 (2H, t, J 6.0 Hz, OCH2CH2), 4.10-3.95 (4H, m, HNCH2 and OCH2CH2), 2.71-2.50 (6H, m, CH3CH2 and C(O)CH2CH2) and 0.99 (3H, t, J 7.0 Hz, CH3) δC (75 MHz; CDCl3) 204.7, 174.3, 172.3, 156.9, 146.2, 139.4, 138.0, 136.8, 129.1, 128.9, 128.8, 128.7, 128.5, 128.4, 128.3, 117.8, 73.3, 67.3, 63.3, 51.5, 50.9, 34.4, 27.9, 19.8 and 13.5.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4](Cl)([CH:10]=[CH2:11])[C:5]([O:8][CH3:9])=[CH:6][N:7]=1.[Cl:13]C1N=CC(OC)=C(Cl)N=1.C([Mg]Br)=C.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CC(C)=O.C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([CH:10]=[CH2:11])[C:5]([O:8][CH3:9])=[C:6]([Cl:13])[N:7]=1
Reactant: COc1cnc(Cl)nc1Cl
Reactant: C=CC1(Cl)NC(Cl)=NC=C1OC
Agent: C=C[Mg]Br
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: C=Cc1nc(Cl)nc(Cl)c1OC
Reaction time: 5 h

Procedure:
2,6-Dichloro-5-methoxy-6-vinyl pyrimidine may be prepared using 2,6-dichloro-5-methoxy pyrimidine, which is commercially available. 2,6-Dichloro-5-methoxy pyrimidine (12.5 g, 69.8 mmol) was combined in a flask with THF (125 mL) and placed in a room temperature water bath. Vinyl magnesium bromide (78 mL, 76.8 mmol) was added in three portions. The mixture was stirred for 5 h. Acetone was added to quench any remaining Grignard reagent. DDQ (19 g, 83.8 mmol) was added to the mixture, and the mixture was stirred overnight. The mixture was then concentrated to remove the THF. Dichloromethane (DCM) was added, triturated, and allowed to stand over the weekend before being filtered, concentrated, and purified by column chromatography on silica gel using a 5-30% ethyl acetate/hexane gradient. This produced the title compound (7.95 g), which was observed to be a light yellow solid that turned grey in light.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]2[C:8]=1[CH:9]=[CH:10][C:11](=[O:18])[NH:12]2.[C:19]([O-:22])(=[O:21])[CH3:20].[Na+].O>CN(C)C=O>[C:19]([O:22][CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]2[C:8]=1[CH:9]=[CH:10][C:11](=[O:18])[NH:12]2)(=[O:21])[CH3:20]
Reactant: CC(=O)[O-]
Reactant: Cc1ccc(OC/C=C/CCl)c2ccc(=O)[nH]c12
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OC/C=C/COc1ccc(C)c2[nH]c(=O)ccc12
Temperature: 120 °C
Reaction time: 6 h
Yield: 67.1 %

Procedure:
5-[(E-4-Chloro-2-butenyl)oxy]-8-methylcarbostyril (16.15 g) was dissolved in dimethylformamide (200 ml), to which sodium acetate (35.0 g) was added and stirred at 120° C. for 6 hours. After the reaction was completed, the reaction mixture was condensed under reduced pressure. Water was added to the condensate and extracted with chloroform. The chloroform phase was dried, and the solvent was removed. The residue was recrystallized from a solvent mixture of chloroform-ether to obtain 11.80 g of 5-[(E-4-acetoxy-2butenyl)oxy]-8-methylcarbostyril as colorless powdery crystals (67.1%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[CH2:16][OH:17])=[O:10])[CH2:5][CH2:4]1.O[C:21]1[C:22]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:23][CH:24]=[CH:25][CH:26]=1.ClC1C=C(O)C=NC=1>>[F:19][C:2]([F:1])([F:18])[C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[CH2:16][O:17][C:21]2[C:22]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:23][CH:24]=[CH:25][CH:26]=2)=[O:10])[CH2:7][CH2:8]1
Reactant: CCOC(=O)c1ncccc1O
Reactant: O=C([C@H]1CC[C@H](C(F)(F)F)CC1)N1CCC[C@H]1CO
Agent: Oc1cncc(Cl)c1
Product: CCOC(=O)c1ncccc1OC[C@@H]1CCCN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 1 of EXAMPLE 29 using [(2S)-1-{[trans-4-(trifluoromethyl)cyclohexyl]carbonyl}pyrrolidin-2-yl]methanol (EXAMPLE 60 Step 1) and ethyl 3-hydroxypicolinate instead of (R)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate and 5-chloropyridin-3-ol.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[F:9][C:10]([F:20])([F:19])[C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1>>[F:9][C:10]([F:19])([F:20])[C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:16][CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:13][CH:12]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: CN1CCC(=O)CC1
Product: CN1CCC(NCc2ccc(C(F)(F)F)cc2)CC1

Procedure:
1-Methyl-4-piperidone (1.13 g, 10.0 mmol, 1.0 eq.), 4-trifluoromethylbenzylamine (1.75 g, 1.0 eq.).
Reaction SMILES: O[Li].O.C([O:6][C:7](=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[O:14][N:13]=1)C.Cl>O.O1CCOCC1>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[O:14][N:13]=[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][C:7]([OH:25])=[O:6])[CH:16]=1
Reactant: CCOC(=O)CCCCc1cc(-c2ccccc2OC)on1
Agent: Cl
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccccc1-c1cc(CCCCC(=O)O)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.4 %

Procedure:
Add a solution of LiOH.H2O (1.83 g, 43.5 mmol) in water (30 mL) to a rapidly stirred solution of 5-[5-(2-methoxy-phenyl)-isoxazol-3-yl]-pentanoic acid ethyl ester (2.64 g, 8.7 mmol) in dioxane (60 mL) and stir overnight at room temperature. After 1 hour, acidify to pH 1 with 5N HCl solution and concentrate to remove the majority of the dioxane. Partition residue between 20% i-PrOH/CHCl3 and 1N HCl solution and separate layers. Backextract from aqueous layer with 20% i-PrOH/CHCl3 and dry combined organic layers over MgSO4, and concentrate to get 2.5 grams of a yellow oil. Recrystallize from EtOAc/hexanes to afford the title compound (1.96 g, 82%). MS (IS) 276 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br.Br[CH2:16][CH2:17][CH2:18][NH2:19].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[NH2:19][CH2:18][CH2:17][CH2:16][N:5]1[CH2:4][CH2:3][C:2]([CH3:1])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6]1
Reactant: NCCCBr
Reactant: CC1(c2ccccc2)CCNCC1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC1(c2ccccc2)CCN(CCCN)CC1
Yield: 18.2 %

Procedure:
4-Methyl-4-phenylpiperidine (1.00 g, 5.70 mmol, 1.00 equiv), 3-bromopropylamine hydrobromide (1.87 g, 8.55 mmol, 1.00 equiv) and potassium carbonate (1.97 g, 14.2 mmol, 2.5 equiv) were stirred in refluxing dioxane (20 mL) for 36 hours. After removal of the solvent, water (50 mL) was added and the pH was adjusted to 11-12 by addition of 1N aqueous NaOH. The mixture was extracted with CH2Cl2 (150 mL+3×100 mL). The combined organic solutions were dried over MgSO4 and concentrated. The residue was purified by flash chromatography (SiO2, CHCl3-MeOH—NH3 (2M in MeOH) 100:20:10) to give 241 mg (18%) of colorless oil, which was characterized spectroscopically.
Reaction SMILES: [CH2:1]1[CH:13]2[N:4]([CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:12]2=[O:14])[C:3](=O)[CH2:2]1.Cl.[NH2:17][OH:18].O.O.O.C([O-])(=O)C.[Na+]>C(O)C.O>[CH2:1]1[CH:13]2[N:4]([CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:12]2=[O:14])[C:3](=[N:17][OH:18])[CH2:2]1
Reactant: O=C1c2ccccc2CN2C(=O)CCC12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1c2ccccc2CN2C(=NO)CCC12
Reaction time: 8 h
Yield: 81.9 %

Procedure:
A mixture consisting of 2.5 g of 1,10a-dihydropyrrolo[1,2-b]isoquinoline-3,10[2H,5H]-dione in 20 ml of 95% ethanol (EtOH), 1.72 g of hydroxylamine hydrochloride in 10 ml of water and 3.7 g of sodium acetate trihydrate in 10 ml of water was refluxed for 7 hours and thereafter allowed to stand overnight at ambient temperature. The product crystallized from the reaction mixture to give 2.2 g of crystals. Recrystallization from 95% EtOH gave 1.4 g of crystals, m.p. 206°-209° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N:14]1[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:20][C:17]2[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=2)[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=Cc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccncc2)CC1
Yield: 100.7 %

Procedure:
Amine preparation: a mixture of 1-BOC-piperazine (2 g), 4-pyridine carboxaldehyde (1.26 g), sodium triacetoxyborohydride (2.96 g) and acetic acid (0.6 mL) was stirred together in dry 1,2-dichloroethane (15 mL) at room temperature. After 4 h the reaction was quenched with saturated NaHCO3 solution and extracted with DCM, dried (Na2SO4), filtered and concentrated in vacuo to give 4-pyridin-4-ylmethyl-piperazine-1-carboxylic acid tert-butyl ester (3 g). Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, which was isolated as the hydrochloride salt.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]3=[O:23])=[CH:9][CH:8]=2)=[CH:3][CH2:2]1.Cl[C:25]1[N:30]=[CH:29][CH:28]=[CH:27][N:26]=1>>[N:26]1[CH:27]=[CH:28][CH:29]=[N:30][C:25]=1[N:1]1[CH2:6][CH2:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]3=[O:23])=[CH:9][CH:8]=2)=[CH:3][CH2:2]1
Reactant: Clc1ncccn1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CCNCC3)cc2)C(=O)O1
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(c4ncccn4)CC3)cc2)C(=O)O1

Procedure:
Using an analogous procedure to that described in Example 25, the TFA salt of Example 2 was reacted on a 1.5 mM scale with 2-chloropyrimidine, to give the title compound. Yield=220 mg, 36%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5]#[N:6].[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=1[CH2:10][Br:11]
Reactant: Cc1ccc(C#N)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)c(Cl)c1
Reaction time: 24 h

Procedure:
A mixture of 3-chloro-4-methyl-benzonitrile (30.0 g, 0.2 mol), N-bromosuccinimide (36.0 g, 0.21 mol) and benzoyl peroxide (100 mg) in 600 mL of CCl4 was refluxed with illumination for 72 h. N-Bromosuccinimide (5.0 g) was added and the reaction was continued for an additional 24 h. The mixture was cooled, filtered and evaporated. Recrystallization from heptane gave pure 2-chloro-4-cyanobenzyl bromide: yield 24.5 g; mp 83°-85° C. Anal. calcd for C8H5BrClN; C, 41.69; H, 2.19; N, 6.07. Found: C, 41.48; H, 1.80; N, 5.76.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:7]([OH:8])[C@H:6]([OH:9])[C@@H:5]([CH2:10][OH:11])[O:4][C@H:3]1[N:12]1[CH:20]=[N:19][C:18]2[C:17](=[O:21])[NH:16][C:15]([NH2:22])=[N:14][C:13]1=2.O.[CH:24]1[C:36]2[CH:35]([CH2:37][O:38][C:39](ON3C(=O)CCC3=O)=[O:40])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]=2[CH:27]=[CH:26][CH:25]=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH:24]1[C:36]2[CH:35]([CH2:37][O:38][C:39]([NH:1][C@@H:2]3[C@@H:7]([OH:8])[C@H:6]([OH:9])[C@@H:5]([CH2:10][OH:11])[O:4][C@H:3]3[N:12]3[CH:20]=[N:19][C:18]4[C:17](=[O:21])[NH:16][C:15]([NH2:22])=[N:14][C:13]3=4)=[O:40])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]=2[CH:27]=[CH:26][CH:25]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2N)c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2NC(=O)OCC2c3ccccc3-c3ccccc32)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.5 %

Procedure:
To 3.31 g (10.61 mmol) of 9-(2-amino-2-deoxy-β-D-glucopyranosyl) guanine was added 72 mL of H2O. To this solution was added a 100 mL 1,4-dioxane solution containing 4.65 g (13.79 mmol) of N-(9-fluorenyl-methoxycarbonyloxy)succinimide. This resulted in a cloudy mixture. To this system was added 0.58 g (6.90 mmol) of NaHCO3. This mixture was stirred for 12 hours at room temperature. At this time, TLC indicated the consumption of starting material and the mixture was concentrated in vacuo to a dry residue. This residue was stirred for 3 hours in 310 mL of Et2O and 145 ml of H2O. The suspension was then filtered and the solid dried in a vacuum oven for 12 hours at 40° C. Thus was obtained 4.28 g (76%) of 9-(2-deoxy-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-β-D-glucopyranosyl)guanine. 1H NMR: (DMSO-δ6): guanine H-8 7.72 (s, 1H), anomeric H-1 5.37 (d, 1H), Fmoc-methine 4.05 (m, 1H). FAB-MS: m/z 535 for (M+1)+.