Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].C(OCC)(=O)CC(OCC)=O.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:28])=[C:21]([CH:23]=[CH:24][C:25](=[O:27])[CH3:26])[CH:22]=1>C(O)C>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:28])=[C:21]([CH:23]2[CH2:3][C:2](=[O:1])[CH2:26][C:25](=[O:27])[CH2:24]2)[CH:22]=1
Reactant: CC(=O)C=Cc1cc(Cl)ccc1C
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(=O)CC(=O)OCC
Product: Cc1ccc(Cl)cc1C1CC(=O)CC(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 20% sodium ethoxide in ethanol (9.5 g) was added at room temperature diethyl malonate (4.5 g) and then added little by little 4-(5-chloro-2-methylphenyl)-3-buten-2-one (5.5 g). The mixture was stirred at room temperature for 30 minutes, refluxed for 2 hours and cooled. The solvent was evaporated, and to the residue was added water. The aqueous layer was washed with ethyl acetate and concentrated. To the residue was added 2M sodium hydroxide (15 ml), and the mixture was refluxed for 2 hours and cooled. To the mixture was added 2.5M sulfuric acid (15 ml) for 15 minutes, and the mixture was refluxed for 30 minutes and cooled. Precipitated crystals were filtered and washed with water and isopropylether to give 5-(5-chloro-2-methylphenyl)cyclohexane-1,3-dione (2.9 g) as colorless crystals.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:8][N:9]=[C:10]([C:13]#[N:14])[C:11]#[N:12])[CH:5]=[CH:6][CH:7]=1.IC1C=C(C=CC=1)N.C(#N)CC#N.O.[NH2:29][NH2:30]>>[NH2:14][C:13]1[C:10](=[N:9][NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=2)[C:11]([NH2:12])=[N:30][N:29]=1
Reactant: N#CC(C#N)=NNc1cccc(I)c1
Reactant: NN
Agent: Nc1cccc(I)c1
Solvent: O
Solvent: N#CCC#N
Product: NC1=NN=C(N)C1=NNc1cccc(I)c1
Yield: 74 %

Procedure:
This compound was prepared using 148 mg (0.5 mmol) of 2-[(3-iodophenyl)hydrazono]-malononitrile, which was derived from 3-iodoaniline (219 mg, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. The hydrazine hydrate was added to the solution at a temperature of 75° C. despite the fact that the starting material had not fully dissolved. The solution cleared briefly and then a precipitate formed. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 122 mg (74%) of the title compound as a mustard coloured solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](O)=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:7]=1.[N:37]1(C2C=CC(C(=O)C)=CC=2)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:6]2[CH:7]=[CH:2][C:3]([N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[CH:4][CH:5]=2)[CH:17]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)c1ccc(N2CCOCC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccc(N5CCOCC5)cc4)ccc3c1)n2C1CCCCC1
Yield: 30 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(4-morpholin-4-yl-phenyl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (37 mg, 30% yield). MS: 533.28 (M+H+); HPLC Procedure A, retention time=10.39 min.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[CH:3]1.C([Li])CCC.CN(C)[CH:20]=[O:21]>C1COCC1.CCOC(C)=O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:4]=[C:3]1[CH:20]=[O:21]
Reactant: Cn1cnc(-c2ccccc2)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccccc2)nc1C=O
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-methyl-4-phenyl-1H-imidazole 42 (0.512 g, 3.24 mmol) in THF (15 mL) at −40° C. was added n-butyllithium (2.40 mL, 3.84 mmol) (1.6 M in hexanes), stirred at −40° C. for 30 min, cooled to −78° C., and N,N-dimethylformamide (0.325 mL, 4.21 mmol) was added. The reaction mixture was warmed to room temperature over 1 h, stirred at room temperature for 2 h, diluted with EtOAc, washed with water (1×), brine (1×), dried over MgSO4, filtered, and concentrated. The crude product was dissolved in DCM (˜20 mL), diluted with hexanes (˜50 mL), and concentrated to a volume of approximately 30 mL. The solution was cooled to 0° C. and the solid was collected by filtration, washed with hexanes, and dried under high vacuum to give 1-methyl-4-phenyl-1H-imidazole-2-carbaldehyde 43. Mass spectrum: calculated for C11H10N2O 186.1; found 187.1 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[C@@H:15]([CH3:32])[CH2:14]2)[C:9](=[O:12])[CH2:10][CH3:11])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40].C(O)C>CN(C=O)C>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][CH2:37][CH2:36][O:30][C:27]1[CH:26]=[CH:25][C:24]([C:23]([N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:13]([N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:9](=[O:12])[CH2:10][CH3:11])[CH2:14][C@@H:15]2[CH3:32])=[O:31])=[CH:29][CH:28]=1)[CH3:43]
Reactant: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(=O)CC)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Reaction time: 0.5 h

Procedure:
(±)-Cis-4-(4-{4-[(4-chloro-phenyl)-propionyl-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-butyric acid ethyl ester was prepared from (±)-cis-N-(4-chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-propionamide. (±)-Cis-N-(4-chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-propionamide (140 mg, 0.31 mmol) was dissolved in DMF (5 mL) at room temperature. Sodium hydride (60% in oil, 32 mg, 0.81 mmol) was added and the mixture allowed to stir 30 min. Ethyl 4-bromobutyrate (207 mg, 1.06 mmol) was added and the reaction was allowed to stir over night. Ethanol was added and the reaction was concentrated in vacuo. The crude residue was purified by silica gel chromatography (80/20 hexanes/ethyl acetate—50/50 hexanes ethyl acetate gradient) to afford the product (171 mg, 0.304 mmol, 98%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8]([OH:10])=O)#[N:2].CCN(C(C)C)C(C)C.[NH2:23][CH2:24][CH:25]([OH:37])[CH2:26][N:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28]1>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8]([NH:23][CH2:24][CH:25]([OH:37])[CH2:26][N:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28]1)=[O:10])#[N:2]
Reactant: N#Cc1cccc(OCC(=O)O)c1
Reactant: NCC(O)CN1CCc2ccccc2C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccc(OCC(=O)NCC(O)CN2CCc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.6 %

Procedure:
To a stirred mixture of 2-(3-cyanophenoxy)acetic acid (100 mg, 0.565 mmol) in DCM (5 mL) was added DIEA (109 mg, 0.85 mmol), 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (116 mg, 0.565 mmol) and BopCl (173 mg, 0.678 mmol). The resulting mixture was stirred at 25° C. for 16 hours until LCMS showed the completion of the reaction. The reaction mixture was quenched by addition of water (20 mL) then extracted with DCM (3×20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-HPLC to afford the desired final product (24 mg, Yield 12%). 1H NMR (400 MHz, METHANOL-d4) δ 7.48 (dd, J1=J2=7.6 Hz, 1H), 7.37 (d, J=7.6 Hz, 1H), 7.25-7.21 (m, 2H), 7.13-7.03 (m, 4H), 4.60 (s, 2H), 4.04-4.00 (m, 1H), 3.71 (s, 2H), 3.44 (d, J=6.0 Hz, 2H), 2.93-2.80 (m, 4H), 2.62 (d, J=5.6 Hz, 2H). LCMS (m/z): 366.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:13]3[C:14]([F:27])=[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:27][C:14]1[C:13]([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:30]4[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=4)[CH:3]=3)[NH:8][CH:9]=2)=[O:12])=[C:18]([F:19])[CH:17]=[CH:16][C:15]=1[NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22]
Reactant: OB(O)c1cccnc1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4cccnc4)cc23)c1F
Temperature: 160 °C

Procedure:
To propane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-0773, prepared as described in Example 1, 65.0 mg, 0.14 mmol) in acetonitrile (4.0 mL) was added pyridine-3-boronic acid (609, 25.0 mg, 0.20 mmol), tetrakis (triphenylphosphine)palladium(0) (11 mg, 1.0% mmol) and aqueous potassium carbonate (1.0 M, 2.0 mL). The reaction was heated to 160° C. for 10 minutes in a CEM Discover microwave instrument. The reaction was poured into water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtrated and concentrated. The desired compound was isolated by silica gel column chromatography (methylene chloride/methanol 5%) to give a white solid (P-0088, 30 mg, 46.9%). MS (ESI) [M+H+]+=457.2.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH3:15])=[CH:13][C:8]=2[NH:7][C:6]1=[O:16].C(=O)([O-])[O-].[Ca+2].[Br-:23].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1>CO.ClCCl>[Br:23][C:11]1[C:12]([O:14][CH3:15])=[CH:13][C:8]2[NH:7][C:6](=[O:16])[N:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH3:17])[C:9]=2[CH:10]=1
Reactant: COc1ccc2c(c1)[nH]c(=O)n2CCN(C)C
Reactant: [Br-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: ClCCl
Product: COc1cc2[nH]c(=O)n(CCN(C)C)c2cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 157 %

Procedure:
To a solution of 1,3-dihydro-1-(2-dimethylaminoethyl)-5-methoxy-2H-benzimidazol-2-one (0.28 g) in methanol (10 ml) and dichloromethane (15 ml) were added calcium carbonate (0.25 g) and benzyltrimethylammonium tribromide (0.49 g). The reaction mixture was stirred at room temperature for 16 hours and the insoluble matter was filtered off. The solvent was then distilled off under reduced pressure and the residue was diluted with 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent: chloroform:methanol=10:1) to give 0.35 g of 6-bromo-1,3-dihydro-1-(2-dimethylaminoethyl)-5-methoxy-2H-benzimidazol-2-one.
Reaction SMILES: C1(O)C=CC=CC=1.[F:8][C:9]([F:27])([F:26])[C:10]1[N:14]2[CH:15]=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH:17]=[CH:18][C:13]2=[N:12][N:11]=1.BrC1C=N[C:32]2N([C:35]([CH:38]([CH3:40])C)=[N:36][N:37]=2)C=1.C([O-])([O-])=O.[Cs+].[Cs+].C(#N)CCC>>[N:37]1[CH:32]=[CH:40][CH:38]=[C:35]([O:25][C:22]2[CH:21]=[CH:20][C:19]([C:16]3[CH:17]=[CH:18][C:13]4[N:14]([C:10]([C:9]([F:8])([F:26])[F:27])=[N:11][N:12]=4)[CH:15]=3)=[CH:24][CH:23]=2)[N:36]=1
Reactant: CC(C)c1nnc2ncc(Br)cn12
Reactant: Oc1ccc(-c2ccc3nnc(C(F)(F)F)n3c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Oc1ccccc1
Solvent: CCCC#N
Product: FC(F)(F)c1nnc2ccc(-c3ccc(Oc4cccnn4)cc3)cn12
Temperature: 140 °C

Procedure:
In a sealable flask, a suspension of the phenol, 4-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)phenol, prepared as described in Example 1 (47 mg, 0.17 mmol), heteroaryl chloride (39 mg, 0.34 mmol), Cs2CO3 (111 mg, 0.34 mmol), and butyronitrile (1 mL) is heated to 140° C. overnight. The reaction is concentrated and purified by RP-HPLC to afford the desired product, 6-(4-(pyridazin-3-yloxy)phenyl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1Cl)[CH3:2].[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(#N)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[NH:22][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH3:2]
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1cccc([N+](=O)[O-])c1Cl
Solvent: CC#N
Product: CCOC(=O)c1cccc([N+](=O)[O-])c1NC1CCCCC1
Yield: 95 %

Procedure:
The crude 2-chloro-3-nitro-benzoic acid ethyl ester was dissolved in acetonitrile (100 mL) and cyclohexylamine (2.5 mL, 21.83 mmol) was added. The mixture was stirred at reflux overnight. After evaporation of solvent, water (100 mL) was added and the precipitates were collected by filtration and dried to give 2-cyclohexylamino-3-nitro-benzoic acid ethyl ester (1.168 g, 95%). MS: 293.16 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.[F:8][C:9]1[CH:19]=[CH:18][C:12]([C:13](OCC)=[O:14])=[CH:11][CH:10]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.O>[F:8][C:9]1[CH:19]=[CH:18][C:12]([C:13](=[O:14])[CH2:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][N:3]=2)=[CH:11][CH:10]=1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: Cc1ccncn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Cc1ccncn1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
To a stirred solution of 4-methylpyrimidine (20.64 g, 0.22 mol) and ethyl 4-fluorobenzoate (36.9 g, 0.22 mol) in dry THF (100 mL) at 0° C. under nitrogen was added lithium bis(trimethylsilyl)amide (1M in THF, 440 mL, 0.44 mol) over a 2 h period. A white precipitate deposited during the addition and this suspension was stirred at room temperature overnight. The reaction was diluted with 100 mL of water and filtered. The filtrate was washed with water (3×) and dried. The solution was diluted with ethyl acetate (100 mL) and the organic phase separated. The aqueous phase was further extracted with ethyl acetate (100 mL). Organic phases were dried (MgSO4) and concentrated and combined with the filtrate to give a combined yield of 47 g (98%) of product. 1H NMR (CDCl3) exists as a 2:1 mixture of enol:keto tautomers: 6 enol form: 5.95 (s, 1H), 6.92 (dd, J=1.2, 5.7 Hz, 1H), 7.06–7.14 (m, 2H), 7.83 (dd, J=5.4, 8.7 Hz, 2H), 8.40 (d, J=5.7 Hz, 1H), 8.8 (s, 1H); keto form: 4.42 (s, 2H), 7.12–7.18 (m, 2H), 7.34 (d, J=4.2 Hz, 1H), 8.06 (dd, J=5.3, 8.8 Hz, 2H), 8.67 (d, J=5.1 Hz, 1H), 9.16 (s, 1H); APESI-MS m/z 215 (M−1)−.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].O1CCCC1.[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH2:22]I)=[O:16])([CH3:13])([CH3:12])[CH3:11].[NH4+].[Cl-]>C(OCC)C.[Cu]I>[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH2:22][CH:1]=[CH2:2])=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: C=C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CI
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: -36 °C
Reaction time: 6 h

Procedure:
Under a nitrogen atmosphere, a solution of vinylmagnesium bromide, 1.0 M in tetrahydrofuran (2.0 mL, 2.0 mmol) was slowly added to a suspension of copper(I) iodide (244.9 mg, 1.28 mmol) in dry diethyl ether (10 mL) at −78° C. Upon completion of the addition, the mixture was warmed to −36° C. for 5 min and was then cooled to −78° C. A solution of (2S)-N-(tert-butoxycarbonyl)-2-(iodomethyl)pyrrolidine (200.0 mg, 0.64 mmol) in dry diethyl ether (5 mL) was added over a period of 10 min. The reaction mixture was warmed to −36° C. and was stirred at −36° C. for 6 h. The resulting dark mixture was treated with saturated aqueous NH4Cl solution (5 mL) and was stirred while warming to ambient temperature. The reaction mixture was extracted with diethyl ether (4×10 mL). The combined ether extracts were dried (Na2SO4), filtered and concentrated under vacuum to yield a pale-yellow oil (200 mg). The product was purified by column chromatography, eluting with hexane:ethyl acetate (1:1). Fractions containing the product were combined and concentrated under vacuum to afford 100 mg (73.6%) of an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)[CH3:2].[P:13]([O-:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN1CCOCC1>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([P:13]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])=[O:20])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: CCOP([O-])OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CCOC(=O)c1ccc(P(=O)(OCC)OCC)cc1
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 67.9 %

Procedure:
A sealed pressure flask, flushed with N2, containing a mixture of 4-bromo-benzoic acid ethyl ester (2a) (5 g, 0.0218 mol), diethyl phosphite (3.093 mL, 0.024 mol), NMM (2.88 mL, 0.0262 mmol) and Pd(PPh3)4 (2.017 g, 0.00175 mol) in acetonitrile (20 mL) was stirred at ambient temperature for 5-10 min, then heated at 90° C. for 18 hours. The reaction mixture was filtered through celite, and the celite was washed with EtOAc (3×30 mL) until the filtrate showed little or no evidence of product by HPLC. The combined organics were dried over Na2SO4 and concentrated on a rotary evaporator. The desired product was purified by silica gel flash chromatography to give a pale yellow oil (4.24 g). 1H NMR (300 MHz, CDCl3) δ (ppm)) 1.36 (m, 6H), 1.42 (t, J=7 Hz, 3H), 4.16 (m, 4H), 4.42 (q, J=7 Hz, 2H), 7.93 (m, 2H), 8.15 (m, 2H). 31P NMR (121 MHz, CDCl3) δ 17.63.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(OC(=O)C)(=O)C.[N+:26]([O-])([OH:28])=[O:27].NC(N)=O.C(C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(O)(=O)C>[C:1]([NH:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:7][C:6]=1[N+:26]([O-:28])=[O:27])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: O=[N+]([O-])O
Agent: NC(N)=O
Agent: O=C(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 62.5 %

Procedure:
Twenty-three grams (0.1 mole) of 4-acetamidobenzophenone, 50 ml. of acetic anhydride and 20 ml. of acetic acid were stirred together. A solution of 90 percent nitric acid (15 ml.), 10 ml. of acetic acid and 0.2 g. of urea was added dropwise to the benzophenone mixture. The reaction mixture was maintained at a temperature of about 50° C. during the nitration. The mixture was stirred at ambient temperature whereupon the mixture became very thick. The thick slurry was poured over ice and the insoluble product was filtered to yield 17.7 g. (62.5 percent yield) of 4-acetamido-3-nitrobenzophenone.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[O:5].[CH3:11][Mg]Br>C(OCC)(=O)C>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]([OH:5])[CH3:11]
Reactant: C[Mg]Br
Reactant: Nc1cccc(Cl)c1C=O
Solvent: CCOC(C)=O
Product: CC(O)c1c(N)cccc1Cl

Procedure:
This compound was prepared using General Method 1 (EXAMPLE 1) from 2-amino-6-chlorobenzaldehyde (45 mg, 0.29 mmol) and methylmagnesium bromide (3 M in ether, 0.24 mL) to afford (±)-(2-amino-6-chlorophenyl)ethanol after flash chromatography (4:1 hexanes:ethyl acetate).
Reaction SMILES: [Cl-].[CH2:2]([O:6][C:7]1[C:12]2[C:13]([O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH2+:21][CH2:20][CH2:19]3)=[N:14][O:15][C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH:3]([CH3:5])[CH3:4].[O:24]1[C:26]2([CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH2:25]1.C(N(CC)C(C)C)(C)C>C(O)C>[CH2:2]([O:6][C:7]1[C:12]2[C:13]([O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([CH2:25][C:26]4([OH:24])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH2:20][CH2:19]3)=[N:14][O:15][C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: C1CC2(CCO1)CO2
Reactant: CC(C)COc1cccc2onc(OCC3CC[NH2+]CC3)c12
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)COc1cccc2onc(OCC3CCN(CC4(O)CCOCC4)CC3)c12
Yield: 67.7 %

Procedure:
A solution of 4-{[(isobutoxy-1,2-benzisoxazol-3-yl)oxy]methyl}piperidinium chloride (40.9 mg, 0.120 mmol, EXAMPLE 8, step 4), 1,6-dioxaspiro[2.5]octane (30.4 mg, 0.266 mmol, Phosphorus and Sulfur and Related Elements 1984, 19, 113) and N,N-diisopropylethylamine (0.10 mL, 0.58 mmol) in ethanol (1 mL) was stirred overnight at room temperature. Solvent was evaporated, and the residual oil was purified by NH gel column chromatography (hexane/ethyl acetate 4:1) to give 34.0 mg (68%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[CH:6]([N:9]=[C:10]=[N:11][CH:12]([CH3:14])[CH3:13])([CH3:8])[CH3:7].NC(N)=N>>[CH2:1]([NH:5][C:10]([NH:11][CH:12]([CH3:14])[CH3:13])=[N:9][CH:6]([CH3:8])[CH3:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: CC(C)N=C=NC(C)C
Agent: N=C(N)N
Product: CCCCNC(=NC(C)C)NC(C)C

Procedure:
A mixture of 33 g of N-butylamine (0.45 mol) and 19 g of diisopropylcarbodiimide (0.15 mol) is refluxed for 3 h 30. GC analysis then shows a conversion of greater than 99.50 of the diisopropylcarbodiimide. The colorless final mixture is concentrated at 60° C. under 20 mbar for 2 h so as to give 29 g of a colorless and virtually odorless liquid of low viscosity, corresponding to the expected guanidine (yield 96.70).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:2]1.Br[CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31].C(N(CC)C(C)C)(C)C>CN(C=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]3[C:25](=[O:26])[C:24]4[C:23](=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:22]3=[O:31])[CH2:14][CH2:15]2)=[N:2]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCN1CCN(c2nsc3ccccc23)CC1
Temperature: 80 °C
Yield: 65.4 %

Procedure:
An 18.01 g sample of 1-(1,2-benzisothiazol-3-yl)piperazine (83.7 mmol), 29.5 g of N-(4-bromobutyl)phthalimide (104.6 mmol) and 36 mL of N,N-diisopropylethylamine (375.4 mmol) were added to 400 mL of dry DMF. The solution was heated at 80° C. for 18 hours, and the solvent was then removed in vacuo. The residue was dissolved in 500 mL of methylene chloride and was washed with saturated aqueous sodium bicarbonate. The combined aqueous layers were re-extracted with 2 portions of methylene chloride. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was crystallized from isopropanol with the addition of 4N HCl/isopropanol to give 23.03 g of the title compound as the hydrochloride, quarter hydrate, m.p. 253°-255° C.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH:2]=[CH2:3].[O:6]1[C:10]2([CH2:15][CH2:14][C:13](=[N:16][S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])[CH2:12][CH2:11]2)[O:9][CH2:8][CH2:7]1>O1CCCC1>[CH2:3]([C:13]1([NH:16][S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])[CH2:12][CH2:11][C:10]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:15][CH2:14]1)[CH:2]=[CH2:1]
Reactant: CC(C)(C)S(=O)N=C1CCC2(CC1)OCCO2
Reactant: C=CC[Mg]Cl
Solvent: C1CCOC1
Product: C=CCC1(NS(=O)C(C)(C)C)CCC2(CC1)OCCO2
Temperature: -78 °C

Procedure:
Allylmagnesium chloride (2 mol/L in tetrahydrofuran, 17.0 mL) is added to a solution of 2-methyl-propane-2-sulfinic acid (1,4-dioxa-spiro[4.5]dec-8-ylidene)-amide (7.0 g) in tetrahydrofuran (70 mL) cooled to −78° C. The resulting solution is stirred with cooling for 3 h and then quenched by the addition of 10% aqueous NH4Cl solution.