Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[OH-].[Na+].S(OC)(O[CH3:19])(=O)=O>C1(C)C=CC=CC=1>[CH3:19][NH:6][C:5]1[CH:7]=[C:8]([CH3:9])[C:2]([CH3:1])=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: Cc1cc(N)c([N+](=O)[O-])cc1C
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CNc1cc(C)c(C)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
A solution of 4,5-dimethyl-2-nitroaniline (2.00 g, 12 mmol) in toluene (25 mL) was added NaOH (1.93 g, 48 mmol). The reaction mass was stirred at 100° C. for 1 h, followed by addition of dimethyl sulphate (4.6 g, 36 mmol) and reaction mass was stirred at RT for 24 h. The reaction mass was quenched in water, extracted with DCM and concentrated to afford 1.5 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 2.11 (s, 3H), 2.24 (d, J=7.8 Hz, 3H), 2.92 (s, 3H), 6.77 (m, 1H), 7.79 (m, 1H), 8.06 (s, 1H); MS (m/z): 180.92 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[Cl:25][C:26]1[CH:27]=[C:28]([S:33](Cl)(=[O:35])=[O:34])[CH:29]=[CH:30][C:31]=1[Cl:32]>C(Cl)Cl>[Cl:25][C:26]1[CH:27]=[C:28]([S:33]([NH:2][C:3]2[CH:8]=[CH:7][C:6]([N:9]3[CH2:10][CH2:11][C:12](=[O:15])[CH2:13][CH2:14]3)=[CH:5][CH:4]=2)(=[O:34])=[O:35])[CH:29]=[CH:30][C:31]=1[Cl:32]
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCN(c2ccc(NS(=O)(=O)c3ccc(Cl)c(Cl)c3)cc2)CC1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 0.5 g (1.9 mmol) of the hydrochloride salt of 1-(4-amino-phenyl)-piperidine-4-one (which was obtained in Example 224) in 10 mL of anhydrous methylene chloride was added 0.99 mL (5.7 mmol) of diisopropylethyl amine. After 10 minutes of stirring, 0.51 g (2.1 mmol) of 3,4-dichlorobenzene sulfonyl chloride was added and the mixture was allowed to stir overnight. The reaction mixture was quenched with water and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate and washed twice with water, twice with brine, dried over sodium sulfate and then concentrated in vacuo. The residue was then purified by flash chromatography (10% EtOAc in hexanes to 50% EtOAc in hexanes) and the title compound was collected as 0.25 g of a yellow solid; 1H NMR (300 MHz, CDCl3) δ 2.55 (t, J=6.09 Hz, 4H), 3.58 (t, J=6.03 Hz, 4H), 6.33 (s, 1H), 6.60-6.88 (m, 2H), 6.95-7.00 (m, 2H), 7.50 (d, J=1.47 Hz, 2H), 7.78-7.79 (m, 1H); MS (ES) m/z: 398.8 (MH+); HRMS found for C17H16Cl2N2O3S: 398.0227.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][NH2:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[K+].[K+].Cl[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1.O>C(O)CC>[C:1]([NH:8][CH2:9][CH2:10][NH:11][C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: Clc1ncccn1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCO
Product: CC(C)(C)OC(=O)NCCNc1ncccn1
Yield: 134.3 %

Procedure:
N-(Boc)ethylenediamine (0.80 g, 5.0 mmol) (Syn. Commun. 1990, 20, 255-264) was dissolved in 1-propanol (12 mL) and treated with K2CO3 (1.2 g, 9.0 mmol), followed by 2-chloropyrimidine (0.91 g, 8.0 mmol), and the mixture was heated to reflux for 24 h. The reaction mixture was poured into H2O (30 mL) and extracted with EtOAc (3×30 mL). The combined organic fractions were dried (MgSO4) and concentrated to give the title compound as a yellow solid (1.6 g): MS (ES) m/e 238.9 [M+H]+.
Reaction SMILES: CC1(C)C[O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=2)=N1.Cl.C([OH:25])C>>[OH:20][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:4]([OH:5])=[O:25])=[CH:14][CH:15]=1
Reactant: CC1(C)COC(c2ccccc2-c2ccc(CO)cc2)=N1
Reactant: CCO
Agent: Cl
Product: O=C(O)c1ccccc1-c1ccc(CO)cc1
Temperature: 25 °C
Yield: 81 %

Procedure:
2.0 g (7.11 mmol) of 4,4-dimethyl-2-(4'-hydroxymethylbiphenyl-2-yl)oxazoline was dissolved in ethanol (30 ml). 2N hydrochloric acid (10 ml) was added thereto, followed by heating under reflux for 3 hours. After the reaction liquid was cooled and concentrated, a saturated aqueous solution of sodium hydrogen-carbonate (100 ml) was added thereto, followed by the extraction with chloroform. After the organic phase was washed with water and dried, it was subjected to vacuum concentration. A 20% aqueous solution of sodium hydroxide (20 ml) and ethanol (20 ml) were added to the residue, followed by heating under reflux for 8 hours. After the reaction liquid was cooled to room temperature and adjusted to pH 6 with hydrochloric acid, it was extracted with chloroform. After the organic phase was washed with water and dried, it was subjected to vacuum concentration. The residue was purified by silica gel column chromatography (a chloroform/methanol system) to give 1.31 g of the title compound (yield 81%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([Cl:10])[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]1=[O:24].C(N(CC)CC)C.[F:32][C:33]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36]>O1CCCC1>[Cl:10][C:6]1[CH:5]=[C:4]([F:11])[C:3]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[C:2]([NH:1][C:35](=[O:36])[C:34]2[CH:38]=[CH:39][C:40]([F:42])=[CH:41][C:33]=2[F:32])[C:7]=1[O:8][CH3:9]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1NC(=O)c1ccc(F)cc1F
Yield: 80.2 %

Procedure:
3-(2-Amino-4-chloro-6-fluoro-3-methoxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (2.0 g, 5.4 mmol) and triethylamine (0.66 g, 6.5 mmol) were dissolved in anhydrous tetrahydrofuran (30 ml) and stirred under ice cooling. To this solution was slowly added 2,4-difluorobenzoyl chloride (0.96 g, 5.4 mmol) and solution refluxed for 2 hr. Another batch of 2,4-difluorobenzoyl chloride (0.19 g, 1.1 mmol) was added and solution refluxed for 2 hr. Solvent was removed in vacuo and the product purified by column chromatography on silica gel using hexane-ethyl acetate (3:1) as the eluent to afford the title compound (2.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:29]1[C:38]2[C:33](=[CH:34][C:35]([O:41][CH3:42])=[C:36]([O:39][CH3:40])[CH:37]=2)[N:32]=[CH:31][CH:30]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:29]4[C:38]5[C:33](=[CH:34][C:35]([O:41][CH3:42])=[C:36]([O:39][CH3:40])[CH:37]=5)[N:32]=[CH:31][CH:30]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cc1)c1cccc2cc(O)ccc12
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc4c(C(=O)Nc5ccc(Cl)cc5)cccc4c3)c2cc1OC
Temperature: 100 °C
Reaction time: 60 h

Procedure:
The 6-hydroxy-naphthalene-1-carboxylic acid(4-chlorophenyl)-amide (Step a, 0.076 g, 0.254 mmol), Cs2CO3 (0.248 g, 0.762 mmol), 4-chloro-6,7-dimethoxy-quinoline (0.114 g, 0.508 mmol) and DMF (0.250 mL) were combined in a screw-cap test tube under N2. The tube was sealed and heated to 100° C. After 60 h at 100° C., the reaction was cooled to RT. The solvent was removed in vacuo, dissolved in EtOAc and washed with saturated aqueous NaHCO3 and brine. The organic layer was dried (Na2SO4), filtered and concentrated. The residue remaining after concentration was dissolved in MeOH and purified by reverse-phase HPLC (pH 10 buffer solvent system). The fractions containing the desired product were concentrated, dissolved in EtOAc, and washed with brine. The organic layer was dried (Na2SO4), filtered and concentrated to afford the title compound as a tan solid. M+H-485.1. Calc'd for C28H31N2O4-484.12.
Reaction SMILES: [CH:1]1[C:9]2[CH:8]=[C:7]3[CH:10]=[CH:11][CH:12]=[CH:13][C:6]3=[CH:5][C:4]=2[CH2:3][CH:2]=1.Br[C:15]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:18]=[C:17]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:16]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:25]([C:17]1[CH:16]=[C:15]([C:2]2[CH2:3][C:4]3[CH:5]=[C:6]4[CH:13]=[CH:12][CH:11]=[CH:10][C:7]4=[CH:8][C:9]=3[CH:1]=2)[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:18]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: C1=Cc2cc3ccccc3cc2C1
Reactant: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(C2=Cc3cc4ccccc4cc3C2)cc(C(C)(C)C)c1
Temperature: 60 °C
Yield: 31.5 %

Procedure:
Benz[f]indene (10.8 g, 0.065 mole) was dissolved in 100 mL of dimethylformamide. 1-Bromo-3,5-di-t-butylbenzene (14 g, 0.052 mole) was added along with palladium acetate (0.3 g), tri-o-tolylphosphine (0.8 g), and triethyl amine (11.0 g). The solution was heated to 60° C. for 3 days. The solution was cooled and washed with 1 N HCl and by saturated sodium bicarbonate. The product was found to be difficult to separate from the residual tri-o-tolylphosphine. After purifying by passing through silica with hexanes three times, and recrystallization from ethanol, followed by three recrystallizations from hexanes, it yielded 5.8 g of 2-(3,5-di-t-butylphenyl)benz[f]indene (26% yield). 1HNMR (CDCl3, 300 MHz δ7.95-7.77 (m, 4H); 7.52-7.37 (m, 5H); 7.23 (s, 1H); 3.99 (s, 2H); 1.43 (s, 18H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[O:23][CH:24]=[CH:25][CH:26]=3)=[CH:18][CH:17]=2)=[CH:13][CH2:14][OH:15])=[CH:8][CH:7]=1.C(P(CCCC)CCCC)CCC.[CH2:40]([O:42][C:43](=[O:56])[C@@H:44]([O:53][CH2:54][CH3:55])[CH2:45][C:46]1[CH:51]=[CH:50][C:49](O)=[CH:48][CH:47]=1)[CH3:41]>C1C=CC=CC=1>[CH2:40]([O:42][C:43](=[O:56])[C@@H:44]([O:53][CH2:54][CH3:55])[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([O:15][CH2:14][CH:13]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[O:23][CH:24]=[CH:25][CH:26]=3)=[CH:18][CH:17]=2)[C:9]2[CH:8]=[CH:7][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[CH:11][CH:10]=2)=[CH:48][CH:47]=1)[CH3:41]
Reactant: OCC=C(c1ccc(-c2ccco2)cc1)c1ccc(-c2ccco2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: c1ccccc1
Product: CCOC(=O)[C@H](Cc1ccc(OCC=C(c2ccc(-c3ccco3)cc2)c2ccc(-c3ccco3)cc2)cc1)OCC
Yield: 71.8 %

Procedure:
Reaction of 3,3-bis-(4-furan-2-yl-phenyl)-prop-2-en-1-ol (460 mg, 1.34 mmol), tributylphosphine (0.50 ml, 2.0 mmol), (2S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (320 mg, 1.34 mmol) and azodicarboxylic dipiperidide (504 mg, 2.0 mmol) in benzene in an identical manner to example 3 gave the title compound (541 mg, 72%).
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[Cl:14][C:15]1[C:20]([NH:21][C:22]([CH3:26])([CH3:25])[CH2:23][OH:24])=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=[CH:17][CH:16]=1.CC(C)=O>C(O)(C)C>[Cl:14][C:15]1[C:20]([NH:21][C:22]([CH3:26])([C:23]([OH:3])=[O:24])[CH3:25])=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)=O
Reactant: CC(C)(CO)Nc1c(Cl)cccc1[N+](=O)[O-]
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CC(C)(Nc1c(Cl)cccc1[N+](=O)[O-])C(=O)O

Procedure:
Jones reagent (2.67 M) is added in aliquots (30 ml, 15 ml, 10 ml, 5 ml) every 15 min to a solution of 2-[N-(6-Chloro-2-nitrophenyl)]amino-2-methyl-1-propanol (IX, EXAMPLE 13, 21.6 g) and acetone (1.65 1) at 0° until the reaction is done as measured by TLC analysis. After 1 hr total time, isopropanol (90 ml) is added and the mixture is allowed to warm to 20°-25°. The mixture is filtered and the solids washed with acetone several times. The combined filtrates are concentrated and partitioned between ether (1.0 1) and potassium hydroxide (10%, 3×100 ml). The basic layer is acidified (3N hydrochloric acid) and extracted with methylene chloride (3×200 ml). The methylene chloride phase is dried over magnesium sulfate, filtered, and concentrated to give the title compound sufficient pure to be used in the next step without additional purification, mp 107°-109°; IR (mineral oil) 3358, 2953, 2924, 1715, 1597, 1496, 1330, 1280, 1231, 1174, 1105 and 747 cm-1 ; NMR (CDCl3) 8.00, 7.61, 7.06, 6.5-7.1 and 1.54 δ; MS (m/z) 258 and 213.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH2:15])[N:12]=[C:11]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=4)=[CH:19][CH:18]=3)[CH:10]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:15][C:13]1[N:14]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)[CH:10]=[C:11]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=3)=[CH:21][CH:22]=2)[N:12]=1
Reactant: COc1ccc(-c2cc(Nc3ccc(Oc4ccnc(C)c4)cc3)nc(N)n2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(Oc2ccc(Nc3cc(-c4ccc(O)cc4)nc(N)n3)cc2)ccn1

Procedure:
The intermediate from Step 1 above is treated with BBr3 in methylene chloride at 0° C. for 12 h. After work-up and purification by a published procedure (J. F. W. McOmie and D. E. West, Org. Synth., Collect. Vol. V, 412 (1973)), the desired compound is obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]2[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]=2)=[CH:3][CH:2]=1.[H][H].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(O)C.O=[Pt]=O>[NH:15]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]=[C:9]1[CH2:8][CH2:7][CH:4]1[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]1
Reactant: [H][H]
Reactant: c1cc(CCC2=NCCCCN2)ccn1
Agent: O=[Pt]=O
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCO
Product: C1CCNC(CCC2CCNCC2)=NC1
Yield: 76.7 %

Procedure:
The 4,5,6,7-tetrahydro-2[2-(4-pyridyl)ethyl]-1H-1,3-diazepine (1.9 g, 0.009M) and PtO2 (0.25 g) in ethanol (20 ml) and 2NHCl (15 ml) was reduced at 45 psig of hydrogen. After the hydrogenation, the solvent was removed and the residue was crystallized from ethanol-ether to give 1.5 g of 4-[2-(4,5,6,7-tetrahydro-1H-1,3-diazepin-2-yl)ethyl]piperidine (60% yield) as dihydrochloride salt.
Reaction SMILES: C[O:2][C:3]([CH:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[C:16](=[O:22])[CH2:15][CH2:14]3)[CH2:6]1)=O.[NH3:23]>CO>[CH3:21][N:17]1[C:18]2[C:13](=[CH:12][C:11]([N:7]3[CH2:6][C@H:5]([C:3]([NH2:23])=[O:2])[O:9][C:8]3=[O:10])=[CH:20][CH:19]=2)[CH2:14][CH2:15][C:16]1=[O:22]
Reactant: COC(=O)C1CN(c2ccc3c(c2)CCC(=O)N3C)C(=O)O1
Reactant: N
Solvent: CO
Product: CN1C(=O)CCc2cc(N3C[C@H](C(N)=O)OC3=O)ccc21
Temperature: 55 °C
Yield: 84 %

Procedure:
To a stirred solution of 3-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2-oxo-oxazolidine-5-carboxylic acid methyl ester (Step 4, 150 mg, 0.49 mmol) in MeOH (1 mL) is added 2.0 M NH3 in MeOH (1 mL, 2.0 mmol). The reaction mixture is then heated at 50-60° C. until all of the solid disappears. Solvent is removed and the residue is dissolved in 20% MeOH/CH2Cl2 and purified by silica gel chromatography (10% MeOH/CH2Cl2) to give the title compound as a white solid (120 mg, 84%), 1H NMR (300 MHz, DMSO) δ 7.85 (br S, 1H), 7.60 (br S, 1H), 7.45-7.08 (m, 3H), 5.01 (dd, 1H), 4.25 (t, 1H), 3.99 (dd, 1H), 3.23 (s, 3H), 2.86 (t, 2H), 2.50 (m, 2H); MS for C14H15N3O4 m/z 290.5 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][CH:29]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][NH:22][CH2:23]3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:26])#[N:2].C=O.[C:32](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][CH:29]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][N:22]([CH3:32])[CH2:23]3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:26])#[N:2]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: N#Cc1cccc(CN2CC[C@H](NS(=O)(=O)c3ccc4c(c3)CNCC4)C2=O)c1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 322.7 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-isoquinoline-7-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]amide (0.29 g, 0.71 mmol) in 10 mL of CH2Cl2 is added 0.27 mL of 37% aqueous formaldehyde. The solution is stirred at room temperature for 1 hour. After this time, sodium triacetoxyborohydride (0.05 g, 0.22 mmol) is added and the resulting mixture is stirred for 18 hours. The reaction mixture is diluted with CH2Cl2 and washed with saturated NaHCO3 solution. The organic phase is dried over anhydrous MgSO4, filtered and concentrated to give 2-methyl-1,2,3,4-tetrahydro-isoquinoline-7-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]amide (0.16 g, 0.71 mmol) as a solid. The crude methylated material is then converted to the title compound as described in EXAMPLE 24, Part C. The imidate intermediate is formed over a period of 18 hours at room temperature. The amidine formation occurred upon heating at reflux for 2 hours. The crude product is purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 60% CH3CN/H2O (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound as a white solid.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:19][OH:20]>>[O:1]([CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14](=[N:19][OH:20])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1CCN(CCCOc2ccccc2)CC1
Agent: Cl
Product: ON=C1CCN(CCCOc2ccccc2)CC1

Procedure:
1-(3-Phenoxypropyl)-4-piperidone oxime is prepared from 1-(3-phenoxypropyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[C:6]([C:11]([O:13][CH3:14])=[O:12])=[N:7][CH:8]=[CH:9][CH:10]=1.N1C=CC=CC=1.[CH2:21]([O:28][C:29](ON1C(=O)CCC1=O)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[CH2:21]([O:28][C:29]([NH:1][CH2:2][CH2:3][NH:4][C:5]1[C:6]([C:11]([O:13][CH3:14])=[O:12])=[N:7][CH:8]=[CH:9][CH:10]=1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1ncccc1NCCN
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ncccc1NCCNC(=O)OCc1ccccc1

Procedure:
A solution of methyl 3-[(2-aminoethyl)amino]pyridine-2-carboxylate (3.9 g, 18.6 mmol) in CHCl3 (25 mL) was treated with pyridine (3 mL, 37.3 mmol) then 1-{[(benzyloxy)carbonyl]oxy}pyrrolidine-2,5-dione (Aldrich, 5.57 g, 22.3 mmol) for ½ hr. The reaction was quenched with water and extracted three times with CHCl3. The organic layer was dried with Na2SO4, filtered and evaporated to give an oil. The crude was purified on silical gel using an ISCO normal phase system and eluting with a gradient of 50% to 90% EtOAc Hexanes. The clean fractions were combined to give the product as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[Br:14]Br>>[Br:14][CH:9]1[CH2:8][CH2:7][O:6][C:5]2[CH:12]=[CH:13][C:2]([Br:1])=[CH:3][C:4]=2[C:10]1=[O:11]
Reactant: BrBr
Reactant: O=C1CCCOc2ccc(Br)cc21
Product: O=C1c2cc(Br)ccc2OCCC1Br

Procedure:
Following the procedure for 449, Step 1, 7-bromo-3,4-dihydro-2H-benzo[b]oxepin-5-one was reacted with bromine to afford the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10]C(OC)=O)=[N:6][C:7]=1[O:8][CH3:9].C([O-])(O)=[O:16].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][OH:16])=[N:6][C:7]=1[O:8][CH3:9]
Reactant: O=C([O-])O
Reactant: COC(=O)Cc1ccc(Br)c(OC)n1
Agent: [Na+]
Solvent: CO
Product: COc1nc(CO)ccc1Br

Procedure:
step d—A solution of 357c (0.060 g), 5% aq. NaHCO3 (2 mL) and MeOH (2 mL) was heated at reflux for 2 h. The reaction mixture was partitioned between H2O and EtOAc and the combined EtOAc extracts were dried, filtered and evaporated in vacuo. The crude product was purified by SiO2 chromatography eluting with 25% EtOAc/hexane to afford 356a.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[S:7][CH2:8][C@@H:9]1[NH:12][C:11](=[O:13])[CH2:10]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:24]1([C@H:30]([N:33]=[C:34]=[O:35])[CH2:31][CH3:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[C:24]1([C@H:30]([NH:33][C:34]([N:12]2[C@@H:9]([CH2:8][S:7][C:2]3[N:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:10][C:11]2=[O:13])=[O:35])[CH2:31][CH3:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC[C@@H](N=C=O)c1ccccc1
Reactant: O=C1C[C@H](CSc2ncccn2)N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@@H](NC(=O)N1C(=O)C[C@@H]1CSc1ncccn1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.8 %

Procedure:
To a solution of 4(R)-(pyrimidin-2-ylsulfanyl-methyl)azetidin-2-one (61.5 mg, 0.315 mmol) in THF (3 mL) at 0° was added dropwise LiHMDS (1M/THF) (0.33 mL, 0.331 mmol). After the reaction mixture was stirred 15 min at 0°, then cooled to −78°, 1(R)-phenylpropyl isocyanate (example 1) (0.53M/toluene, 0.63 mL, 0.315 mmol) was added dropwise and the mixture was warmed to room temperature and stirred for 1.5 h. The reaction mixture was quenched with H2O and diluted with EtOAc. The organic phase was washed with H2O and brine, dried (MgSO4), filtered and evaporated. The product was purified by flash chromatography (SiO2, 30% EtOAc/hexane) to give 2-oxo-4(R)-(pyrimidin-2-ylsulfanylmethyl)azetidine-1-carboxylic acid (1(R)-phenylpropyl)amide (75 mg, 67% yield) as a viscous gum. 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=4.8 Hz, 2H), 7.29-7.17 (m, 5H), 6.94 (t, J=4.8 Hz, 1H), 6.82 (d, J=8.3 Hz, 1H) 4.71 (q, J=7.6 Hz, 1H), 4.33-4.28 (m, 1H), 4.03 (dd, J=14.2, 3.3 Hz, 1H), 3.39 (dd, J=14.2, 8.3 Hz, 1H), 3.03 (dd, J=16.0, 5.6 Hz, 1H), 2.89 (dd, J=16.0, 3.0 Hz, 1H), 1.83-1.75 (m, 2H), 0.86 (t, J=7.3 Hz, 3H); IR (neat) υ 1758, 1692 cm−1; FAB MS m/z 357.3 (MH+); HRMS calcd. for C18H21N4O2S (MH+) 357.1385, found 357.1379.
Reaction SMILES: C[Si](C1([B:10]([Cl:12])[Cl:11])C=CC=C1)(C)C.[CH3:13][Si:14]([C:17]1[CH:18]([Si](C)(C)C)[C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH3:16])[CH3:15].C(=O)=O.B(Cl)(Cl)Cl>>[CH3:13][Si:14]([C:17]1[CH:18]([B:10]([Cl:12])[Cl:11])[C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH3:16])[CH3:15]
Reactant: C[Si](C)(C)C1(B(Cl)Cl)C=CC=C1
Reactant: C[Si](C)(C)C1=Cc2ccccc2C1[Si](C)(C)C
Agent: ClB(Cl)Cl
Agent: O=C=O
Product: C[Si](C)(C)C1=Cc2ccccc2C1B(Cl)Cl
Temperature: -30 °C
Reaction time: 3 h

Procedure:
In a manner similar to the preparation of compound 2, 12.3 g (0.047 mol) of compound 13 were introduced into a round-bottomed flask which was cooled to -30° C. and had a reflux condenser cooled with dry ice. 5.6 g (0.046 mol) of BCl3 were added to this. When the addition was complete, the cooling bath was removed and the reaction mixture warmed to room temperature and was stirred for 3 hours. The temperature was then raised to 55° C. for 6 hours. After cooling and removal of the volatile contents in vacuo, the crude product was obtained. Distillation under a high vacuum gave the purified product, the main isomer of which was identified as follows: