Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11]([O:15][C:16]([NH:18][CH:19]([C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)[C:20]([O:22][C@@H:23]1[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1)=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12]>CCOC(C)=O>[Cl-:1].[C:11]([O:15][C:16]([NH:18][CH:19]([C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)[C:20]([O:22][C@@H:23]1[CH:28]2[CH2:27][CH2:26][N+:25]([CH2:2][C:3](=[O:4])[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)([CH2:30][CH2:29]2)[CH2:24]1)=[O:21])=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1cccs1
Reactant: O=C(CCl)c1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(C(=O)O[C@H]1C[N+]2(CC(=O)c3ccccc3)CCC1CC2)c1cccs1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 48 %

Procedure:
2-Chloro-1-phenylethanone (43.0 mg, 0.28 mmol) was added to a solution of (R)-quinuclidin-3-yl 2-(tert-butoxycarbonylamino)-2-(thiophen-2-yl)acetate (102 mg, 0.28 mmol) in EtOAc (3 ml). The reaction was stirred at RT for 20 hours. The solvent was evaporated, and the crude was triturated with Et2O (2 ml) and dried under vacuum to obtain (3R)-3-(2-(tert-butoxycarbonylamino)-2-(thiophen-2-yl)acetoxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane chloride (70 mg, 48.3% yield).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[N:10][C:9]([C:12]([OH:14])=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[N:17]1[CH:18]=[CH:19][N:20]2[CH:25]=[CH:24][N:23]=[C:22]([N:26]3[CH2:30][CH2:29][C@@H:28]([NH2:31])[CH2:27]3)[C:21]=12.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:17]1[CH:18]=[CH:19][N:20]2[CH:25]=[CH:24][N:23]=[C:22]([N:26]3[CH2:30][CH2:29][C@@H:28]([NH:31][C:12]([C:9]4[N:10]=[CH:11][N:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:8]=4)=[O:14])[CH2:27]3)[C:21]=12
Reactant: O=C(O)c1ncn(-c2ccccc2)n1
Reactant: N[C@@H]1CCN(c2nccn3ccnc23)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H]1CCN(c2nccn3ccnc23)C1)c1ncn(-c2ccccc2)n1
Reaction time: 0.05 h
Yield: 39.7 %

Procedure:
1-Phenyl-1,2,4-triazole-3-carboxylic acid (1.2 g, 6.3 mmol), (3R)-1-imidazo[1,2-a]pyrazin-8-ylpyrrolidin-3-amine dihydrochloride (2.0 g, 7.4 mmol), and diisopropylethylamine (13 mL, 75 mmol) were combined together in 50 mL DMF. To this mixture was added HATU (2.5 g, 6.6 mmol). After stirring 3 minutes, LCMS of an aliquot indicated the reaction was complete. DIPEA and most of the DMF were removed under reduced pressure. The residue was diluted in 400 mL EtOAc and washed with 50 mL saturated NaH2PO4. It was determined that a large amount of the desired product was present in the organic phase, therefore it was extracted with 400 mL 10 vol % i-PrOH/CHCl3. The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (SiO2, 2-5% MeOH/dichloromethane) to provide 936 mg of the desired product (39% yield). 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1 H), 7.74 (td, J=1.1, 7.5 Hz, 2 H), 7.56-7.48 (m, 4 H), 7.47-7.40 (m, 2 H), 7.37 (d, J=8.2 Hz, 1 H), 7.33 (d, J=4.3 Hz, 1 H), 5.00-4.80 (m, 1H), 4.50-4.35 (br, 1 H), 4.30-4.15 (br, 3 H), 3.45-3.30 (m, 1H), 2.90-2.75 (m, 1 H), 2.50-2.38 (m, 1 H), 2.25-2.15 (m, 1 H). MS: (ES) 375.2 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:22])(C)(C)C.CC1(C)O[C:29]([C:31]2[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=2)[C:34]#[N:35])=[CH:28][C:27](=[O:39])O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:20]([C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:29]([C:31]4[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=4)[C:34]#[N:35])[CH2:28][C:27](=[O:39])[NH:22][C:9]=3[CH:10]=2)=[CH:19][CH:18]=1)[CH3:21]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CCc1ccc(-c2ccc(NC(=O)OC(C)(C)C)c(N)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(-c2ccc3c(c2)NC(=O)CC(c2cccc(C#N)c2)=N3)cc1

Procedure:
Prepared from (3-amino-4′-ethyl-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G8) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a beige solid (67 mg).
Reaction SMILES: [CH3:1][N:2]([CH2:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[C:25]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C1COCC1>CO>[CH3:1][N:2]([CH2:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH:25]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:23]=2)[CH:15]=[CH:16][CH:17]=1)[C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: CCOC(=O)C(=Cc1ccc(-c2cccc(CN(C)C(=O)c3ccccc3)c2)cc1)C(=O)OCC
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)C(Cc1ccc(-c2cccc(CN(C)C(=O)c3ccccc3)c2)cc1)C(=O)OCC
Reaction time: 20 h

Procedure:
700 mg (1.5 mmol) of diethyl 2-(3′-{[methyl-(1-phenylmethanoyl)amino]methyl}biphenyl-4-ylmethylene)malonate, 7 ml of THF and 1 ml of methanol are introduced into a three-necked flask under a stream of nitrogen. The reaction medium is degassed, 80 mg of palladium-on-charcoal (5%) are introduced and the mixture is hydrogenated under atmospheric pressure at room temperature for 20 hours. The reaction medium is filtered through Celite and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (80/20). After evaporation of the solvents, 450 mg (63%) of the desired product are collected.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][Cl:8].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:2][CH2:3][CH2:4][N:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][CH2:7][Cl:8]
Reactant: ClCCNCCCl
Reactant: BrCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: ClCCN(CCCl)Cc1ccccc1
Reaction time: 8 h

Procedure:
An ice bath is used to cool a mixture of 150 g of N,N-bis(2-chloroethyl)amine hydrochloride and 100 ml of benzyl bromide in 1000 ml of DMF and then 120 ml of triethylamine are added dropwise and the mixture is left with stirring at AT overnight. The reaction mixture is concentrated under vacuum, the residue is taken up in water and extracted 3 times with ether, the organic phases are dried over Na2SO4 and the solvent is evaporated under vacuum. This gives 113 g of the expected product.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:16]#[C:17][NH2:18]>ClCCCl>[C:17]([NH:18][C:8]([NH:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)#[N:16]
Reactant: C(=Nc1ccccc1)=NC1CCCCC1
Reactant: N#CN
Solvent: ClCCCl
Product: N#CNC(=Nc1ccccc1)NC1CCCCC1

Procedure:
A solution of 1.8 g N-cyclohexyl-N'-phenylcarbodiimide [prepared in accordance with Tetrahedron Letters 26, 1661 (1985) in 20 ml of 1,2-dichloroethane is reacted with 0.42 g of cyanamide and the reaction mixture is worked up as described in Example 1. The viscous oily crude product is chromatographed on silica gel (elution with a 4:1 mixture of methylene chloride/diethyl ether), affording a crystalline product which melts at 147°-147.5° C. (recrystallisation from ethyl acetate).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[CH:17]=2)=[O:14])=[CH:4][CH:3]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1>>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[CH2:12][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([C:33]3[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=3)=[CH:3][CH:4]=2)=[CH:17][C:18]=1[N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1
Reactant: COc1ccc(NC(=O)Cc2ccc(Br)c3ccccc23)cc1N1CCN(C)CC1
Reactant: OB(O)c1cccnc1
Product: COc1ccc(NC(=O)Cc2ccc(-c3cccnc3)c3ccccc23)cc1N1CCN(C)CC1

Procedure:
The title compound was prepared from 4-bromo-N-[4-methoxy-3-(4-methyipiperazin-1-yl)phenyl]-1-naphthylacetamide (E9) and 3-pyridylboronic acid using a similar procedure to Example 4 as a white solid (32%).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13](=[O:15])[CH3:14])[CH:12]=1)=[O:6]>O1CCOCC1>[BrH:1].[CH3:3][O:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13](=[O:15])[CH2:14][Br:1])[CH:12]=1)=[O:6]
Reactant: BrBr
Reactant: COC(=O)c1cncc(C(C)=O)c1
Solvent: C1COCCO1
Product: Br
Product: COC(=O)c1cncc(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 157.1 %

Procedure:
Bromine (6.0 g) was added slowly to a solution of 5-acetyl-3-pyridinecarboxylic acid methyl ester (6.0 g) in dioxane (50 ml) at room temperature. The mixture was stirred at room temperature for 1 hour and then heated at 60°-70° C. for 5 hours. The resulting precipitate was collected by filtration to afford 5-bromoacetyl-3-pyridinecarboxylic acid methyl ester hydrobromide (10.0 g).
Reaction SMILES: [CH:1]([Si:4](C1C=CC=CC=1)(C1C=CC=CC=1)[Si:5](C(C)C)(C1C=CC=CC=1)[C:6]1[CH:11]=CC=C[CH:7]=1)([CH3:3])[CH3:2].[SiH3][SiH3].[Cl-:35].[Al+3].[Cl-:37].[Cl-:38].[ClH:39]>CC(C)=O.C1C=CC=CC=1>[CH:1]([Si:4]([Cl:39])([Cl:38])[Si:5]([CH:6]([CH3:11])[CH3:7])([Cl:37])[Cl:35])([CH3:3])[CH3:2]
Reactant: Cl
Reactant: CC(C)[Si](c1ccccc1)(c1ccccc1)[Si](c1ccccc1)(c1ccccc1)C(C)C
Reactant: [Cl-]
Agent: [Al+3]
Agent: [SiH3][SiH3]
Solvent: c1ccccc1
Solvent: CC(C)=O
Product: CC(C)[Si](Cl)(Cl)[Si](Cl)(Cl)C(C)C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
A 500 ml three necked flask was charged with 300 ml of dry benzene and 48.5 g (0.11 mole) of 1,2-diisopropyl-1,1,2,2-tetraphenyldisilane, and the disilane was uniformly dissolved. To the solution was added 1.5 g of anhydrous aluminium chloride While a dry hydrogen chloride gas was introduced into the benzene solution through a needle tube, the flask was heated for a short time to initiate the reaction. After the reaction once began, generation of heat continued for about 20 minutes After the termination of the exothermic reaction, the introduction of the hydrogen chloride gas was stopped. After 2 ml of dry acetone was added in order to inactivate the aluminium chloride, the solvent was distilled away from the reaction mixture. The residue was subjected to a fractional distillation to give 27 g (0.095 mole, 86% yield) of 1,2-diisopropyl-1,1,2,2-tetrachlorodisilane in a colorless clear liquid (b.p. 55° to 57° C./0.45 Torr).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([C:15]3[C:16]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:14])=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:31]([OH:33])=O)[CH3:2].Cl.[NH2:35][C@@H:36]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:37]([NH:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38].CCN(C(C)C)C(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:40]([NH:39][C:37](=[O:38])[C@@H:36]([NH:35][C:31]([C:4]1[N:3]([CH2:1][CH3:2])[C:11]2[C:6]([CH:5]=1)=[CH:7][C:8]([NH:12][C:13]([C:15]1[C:16]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=3)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:14])=[CH:9][CH:10]=2)=[O:33])[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: N[C@H](C(=O)NCc1ccccc1)c1ccccc1
Reactant: CCn1c(C(=O)O)cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc21
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(C(=O)N[C@H](C(=O)NCc2ccccc2)c2ccccc2)cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc21
Reaction time: 8 h
Yield: 71 %

Procedure:
1-Ethyl-5-[(4′-trifluoromethyl-biphenyl-2-carbonyl)amino]-1H-indole-2-carboxylic acid (0.05 g, 0.11 mmol) and (S)-2-Amino-N-benzyl-2-phenyl-acetamide hydrochloride (0.031 g, 0.11 mmol) were combined in DCM (3 mL) and DIEA (1.1 mL) was added to the above mixture. PyBroP (0.077 g, 0.17 mmol) was added to the above mixture in one portion. The mixture which was resulted was stirred overnight. The crude mixture was then purified by HPLC to furnish the desired product (52.7 mg). HPLC retention time 16.892 min.; Mol. Wt. (calc) 674.7; MS (found) 675.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])=[CH:4][CH:3]=1.[Br:15]Br>C(Cl)(Cl)Cl>[Br:15][CH:10]1[C:9](=[O:14])[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: BrBr
Reactant: O=C1CCCCC1c1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: O=C1C(Br)CCCC1c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 107.2 %

Procedure:
2-(4-Chloro-phenyl)-cyclohexanone (51 mg, 0.24 mmol) was dissolved in chloroform (1 mL). To this solution bromine (41.0 mg, 0.26 mmol) in chloroform (0.5 mL) was added drop wise at room temperature. The reaction was stirred for 1½ hours at room temperature. The solvent was removed under reduced pressure to yield the crude title compound (74 mg) which was used directly in the next step without further purification.
Reaction SMILES: C[N:2]([CH3:19])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([N:13]([CH2:17][CH3:18])[C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1)=O.N[C:21]1[C:25]([C:26]#[N:27])=C[NH:23][N:22]=1.P(=O)(O)(O)O>O.C(O)C>[CH3:18][CH2:17][N:13]([C:14]([CH3:15])=[O:16])[C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:5]2[N:23]3[N:22]=[CH:21][C:25]([C:26]#[N:27])=[C:19]3[N:2]=[CH:3][CH:4]=2)[CH:8]=1
Reactant: N#Cc1c[nH]nc1N
Reactant: CCN(C(C)=O)c1cccc(C(=O)C=CN(C)C)c1
Agent: O=P(O)(O)O
Solvent: CCO
Solvent: O
Product: CCN(C(C)=O)c1cccc(-c2ccnc3c(C#N)cnn23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethylacetamide (2.6 g, 0.01 mol) and 3-amino-4-cyanopyrazole (1.08 g, 0.01 mol) were dissolved in the mixture of water (35 cm3) and ethanol (20 cm3). Phosphoric acid (85%) (0.67 cm3, 0.01 mol) was then added and the mixture was stirred at room temperature for about 8 hours. The reaction mixture was then cooled to about 5° C. and the crystalline product that formed was collected, washed with water and dried at about 60° C. to yield zaleplon (2.95 g, 96.7%) in 99.09% purity as determined by HPLC.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[C:25]([O:15][CH:12]1[CH2:11][CH2:10][N:9]([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:17][CH:16]=2)[CH2:14][CH2:13]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=[N+]([O-])c1ccc(CN2CCC(O)CC2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1)c1ccccc1
Yield: 77.5 %

Procedure:
0.3 g (0.00127mol) of 1-(4-nitro-benzyl)-piperidin-4-ol and 0.356 ml (0.00254 mol) of triethylamine were dissolved in 10 ml of toluene, treated with 0.177 ml (0.0015 mol) of benzoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 0.335 g (78%) of 1-(4-nitro-benzyl)-piperidin-4-yl benzoate was obtained as yellow crystals. MS: me/e (% basic peak)=340 (C19H20O4+, 3.5), 235 (5), 218 (41), 105 (26), 82 (100).
Reaction SMILES: [BH4-].[Li+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:27](OC)=[O:28])=[C:8]2[C:12]=1[N:11]=[C:10]1[N:13]([C:17]3[C:18]([CH3:26])=[N:19][C:20]([N:23]([CH3:25])[CH3:24])=[CH:21][CH:22]=3)[CH2:14][CH2:15][CH2:16][N:9]21>O1CCCC1>[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[C:18]([CH3:26])=[N:19][C:20]([N:23]([CH3:25])[CH3:24])=[CH:21][CH:22]=4)[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH2:27][OH:28])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(N(C)C)nc1C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(N(C)C)ccc1N1CCCn2c1nc1c(Cl)ccc(CO)c12
Temperature: 40 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
Lithium borohydride (7.43 mg, 3.41 mmol) was added to a stirred solution of methyl 9-chloro-1-[6-(dimethylamino)-2-methylpyridin-3-yl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (341 mg, 0.853 mmol) in tetrahydrofuran (5.0 mL) at room temperature, and the mixture was stirred at 40° C. for 20 hr. The reaction was quenched by aqueous saturated ammonium chloride at 0° C., concentrated in vacuo and the precipitate was collected by filtration, washed with water, diisopropyl ether to give the title compound as a colorless powder (317 mg, 0.853 mmol, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+].O.Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(C)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1c(C)cc(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.4 %

Procedure:
To a solution of methyl 5-bromo-2-methoxy-3-methyl-benzoate (2.6 g, 10.0 mmol, 1.0 eq) in THF (20 mL) was added an aqueous solution of NaOH (2M, 20 mL, 40 mmol, 4.0 eq). The mixture was stirred at room temperature for 5 h. Water was added and the aqueous layer was acidified to pH 9 by addition of 1M HCl. The THF was removed in vacuo and the aqueous layer was further acidified to pH 4-5 with 1M HCl. The solid that precipitated from the reaction was collected by filtration and dried to give the title compound as a white solid (1.8 g, 73%).
Reaction SMILES: [F:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:11]=2[O:19][CH3:20])[CH2:3]1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[S:32][C:31]([C:33](OC)=[O:34])=[C:30](/[N:37]=[CH:38]/N(C)C)[CH:29]=2)=[CH:24][CH:23]=1.C1(O)C=CC=CC=1>C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[S:32][C:31]3[C:33](=[O:34])[N:16]([C:13]4[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][N:4]5[CH2:5][CH2:6][CH:2]([F:1])[CH2:3]5)=[C:11]([O:19][CH3:20])[CH:12]=4)[CH:38]=[N:37][C:30]=3[CH:29]=2)=[CH:26][CH:27]=1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCN1CCC(F)C1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1/N=C/N(C)C
Solvent: ClCCl
Solvent: Oc1ccccc1
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCCN1CCC(F)C1
Temperature: 200 °C
Reaction time: 0.75 h
Yield: 11.5 %

Procedure:
3-Fluoro-1-[2-(2-methoxy-4-nitrophenoxy)ethyl]pyrrolidine (0.0442 g, 0.1740 mmol) and methyl 5-(4-chlorophenyl)-3-{[(1E)-(dimethylamino)methylidene]amino}thiophene-2-carboxylate (0.056 g, 0.1740 mmol) were charged to a flask. Phenol (1 g) was added and the reaction heated to 200° C. The reaction was stirred for 45 min until all starting material was gone. The mix was then cooled to RT, diluted with CH2Cl2 (30 mL) and washed with 1N NaOH (2×30 mL), water (1×30 mL), brine (1×30 mL), dried over MgSO4, filtered, and concentrated. The residue was purified on a chromatatron (98:2 CH2Cl2:MeOH) to give 0.010 g (0.020 mmol, 11%) of the product as a tan solid. 1H NMR (CDCl3) δ 8.13 (s, 1H), 7.65 (d, 2H, J=8.3 Hz), 7.52 (s, 1H), 7.43 (d, 2H, J=8.4 Hz), 7.00 (d, 1H, J=8.4 Hz), 6.93 (m, 2H), 5.29-5.13 (m,1H), 4.23 (t, 2H, J=5.7 Hz), 3.88 (s, 3H), 3.12-2.93 (m, 5H), 2.68 (bs, 1H), 2.25-2.06 (m, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11]Cl)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl.[Cl:14][C:15]1[CH:16]=[N:17][C:18](=[O:21])[NH:19][CH:20]=1.C(N(CC)CC)C.CC(C)=O>ClCCl>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][N:19]2[CH:20]=[C:15]([Cl:14])[CH:16]=[N:17][C:18]2=[O:21])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(OCCl)cc1
Reactant: O=c1ncc(Cl)c[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(=O)c1ccc(OCn2cc(Cl)cnc2=O)cc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 6 by adding a solution of 4-acetyl-1-(chloromethoxy)benzene [see Preparation 7] (2.2 mmol) in dichloromethane (5 ml) to a solution of 5-chloropyrimidin-2-one hydrochloride (2.2 mmol) and triethylamine (4.4 mmol) in dichloromethane (20 ml). The product was the desired N-alkylated isomer; yield: 0.60 g (100%), m.p. 182° C. (acetone). (Found C56.38 H4.15 Calc. for C13H11ClN2O3 : C56.02; H3.99) 1H NMR (CDCl3) δ 2.50 (Me), 5.82 (CH2), 7.0 and 7.8 (H-4 and H-6, respectively, J 3 Hz). [70 eV, m/z, % rel. int.)]: 278 (7,M), 145 (31), 143 (100), 136 (18), 121 (33), 116 (22), 93 (15).
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1.[CH:20]1(B(O)O)[CH2:22][CH2:21]1.N1C=CC=CC=1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH:20]1([N:6]2[CH2:5][CH2:4][N:3]([C@@H:7]3[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]3)[C:2]2=[O:1])[CH2:22][CH2:21]1
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N2CCNC2=O)C1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](N2CCN(C3CC3)C2=O)C1
Temperature: 40 °C
Reaction time: 48 h
Yield: 27 %

Procedure:
To a solution of (R)-tert-butyl 3-(2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (365) (10.0 g, 31.17 mmol), cyclopropylboronic acid (6.39 g, 74.35 mmol) and pyridine (8.82 g, 111.5 mmol) in anhydrous DMF (100 mL) was added Cu(OAc)2 (6.75 g, 37.17 mmol). The resulting mixture was stirred at 40° C. under O2 atmosphere (balloon) for 48 hours. After quenched with NH3.H2O (10 mL), the mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL×3). The organic layers were combined, washed with brine, dried, concentrated, and subjected to silica flash column chromatography using 0 to 70% EtOAc in PE to isolate (R)-tert-butyl 3-(3-cyclopropyl-2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (391) (2.6 g, 23%) as a light yellow oil.
Reaction SMILES: C(N(CC)CC)C.F[C:9]1[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[N:13][CH:14]=1.[C@@H:18]12[NH:25][C@@H:22]([CH2:23][CH2:24]1)[CH2:21][N:20]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:19]2>CS(C)=O.C(OCC)(=O)C>[N+:15]([C:12]1[N:13]=[CH:14][C:9]([N:25]2[CH:18]3[CH2:24][CH2:23][CH:22]2[CH2:21][N:20]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:19]3)=[CH:10][CH:11]=1)([O-:17])=[O:16]
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CC[C@@H](C1)N2
Reactant: O=[N+]([O-])c1ccc(F)cn1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC2CCC(C1)N2c1ccc([N+](=O)[O-])nc1
Temperature: 80 °C
Yield: 73.4 %

Procedure:
Triethylamine (6.87 mL, 49.3 mmol) was added to a stirred solution of 5-fluoro-2-nitropyridine (700 mg, 4.93 mmol) and (1R,5S)-tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (1.05 g, 4.93 mmol) in 8 mL of DMSO at room temperature. The reaction mixture was heated to 80° C. for 2 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with, saturated ammonium chloride, water (3×), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 1.21 g (73.5%) of tert-butyl 8-(6-nitropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate as yellow solid.