Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)O1.Br[C:27]1[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:35])[F:34])=[N:31][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[F:34][C:33]([F:36])([F:35])[C:30]1[N:31]=[CH:32][C:27]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:23])[CH3:24])(=[O:20])=[O:21])[CH2:12]3)=[CH:28][CH:29]=1
Reactant: FC(F)(F)c1ccc(Br)cn1
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(-c3ccc(C(F)(F)F)nc3)cc2C1

Procedure:
To a solution of N-[(2S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (190 mg, 0.52 mmol) in dry 1,4 dioxane (5 ml), polymer supported Pd(PPh3)4 (10 mg, 0.5 mmol/g, 0.005 mmol) was added along with 5-bromo-2-(trifluoromethyl)pyridine (176 mg, 0.78 mmol) and 500 μl of a 2M Na2CO3 solution in water. The resulting mixture was heated at 90° degrees for 3 hours. Then after cooling the resin was removed by filtration and then the solvent was removed under reduced pressure. The residue was taken up with DCM, washed with water and loaded on a 25M+ silica cartridge eluating with a cyclohexane/AcOEt 75/25 mixture. 150 mg of title compound were recovered as whitish solid (75%). Due to the use of chiral Intermediate 7, the final compound is believed to be N-{(2S)-5-[6-(trifluoromethyl)-3-pyridinyl]-2,3-dihydro-1H-inden-2-yl}-2-propanesulfonamide.
Reaction SMILES: Cl.N[C@@H]1C(=O)NC2C=CC=CC=2OC1.C([O-])(=O)C.[Na+].C1(CCC(=O)C(OCC)=O)CCCCC1.[CH2:35]([O:37][C:38]([CH:40]([NH:49][CH:50]1[C:56](=[O:57])[NH:55][C:54]2[CH:58]=[CH:59][CH:60]=[CH:61][C:53]=2[O:52][CH2:51]1)[CH2:41][CH2:42][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)=[O:39])[CH3:36].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:69][C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71].[I-].[K+]>[Ni].O.C(OCC)(=O)C.CN(C)C=O.C(O)(=O)C.C(O)C>[CH2:35]([O:37][C:38]([CH:40]([NH:49][CH:50]1[C:56](=[O:57])[N:55]([CH2:69][C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[C:54]2[CH:58]=[CH:59][CH:60]=[CH:61][C:53]=2[O:52][CH2:51]1)[CH2:41][CH2:42][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)=[O:39])[CH3:36]
Reactant: CC(C)(C)OC(=O)CCl
Reactant: CCOC(=O)C(CCC1CCCCC1)NC1COc2ccccc2NC1=O
Agent: [Ni]
Agent: CC(=O)[O-]
Agent: CCOC(=O)C(=O)CCC1CCCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)C(CCC1CCCCC1)NC1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O

Procedure:
A mixture of 3(S)-amino-2,3,4,5-tetrahydro-1,5-benzoxazepine-4-one hydrochloride (2 g), ethanol (100 ml), sodium acetate (0.8 g), acetic acid (0.6 g), molecular sieves 4A (5 g) and ethyl 4-cyclohexyl-2-oxo-butyrate (5 g) is catalytically hydrogenated over Raney nickel at room temperature under atmospheric pressure. After the absorption of hydrogen ceases, the catalyst is removed by filtration and the filtrate is evaporated in vacuo. To the residue are added water (50 ml) and ethyl acetate (200 ml), and the mixture is agitated thoroughly. The ethyl acetate layer is dried over anhydrous magnesium sulfate and evaporated in vacuo to yield an oily residue containing 3-(1-ethoxycarbonyl-3-cyclohexylpropyl)amino-2,3,4,5-tetrahydro-1,5-benzoxazepine-4-one. A mixture of this oil, potassium carbonate (4 g), tert-butyl chloroacetate (3 g), potassium iodide (0.2 g) and N,N-dimethylformamide (20 ml) is stirred overnight at room temperature, and then diluted with a mixture of water (300 ml) and ethyl acetate (200 ml). The organic layer is separated, dried over anhydrous magnesium sulfate and evaporated in vacuo to yield an oil, which is purified by silica gel column chromatography using hexaneethyl acetate (4:1) as an eluant to yield tert-butyl 3-(1-ethoxycarbonyl-3-cyclohexylpropyl)amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (1 g) as a colorless oil.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].CN(C)C1C=C(N(C)C)C=CC=1[C:16]1(C2C=CC(N(C)C)=CC=2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:18](=[O:19])[O:17]1>S(=O)(=O)(O)O>[N+:1]([C:22]1[CH:21]=[C:20]2[C:25]([CH2:16][O:17][C:18]2=[O:19])=[CH:24][CH:23]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CN(C)c1ccc(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3ccccc32)cc1
Agent: O=S(=O)(O)O
Product: O=C1OCc2ccc([N+](=O)[O-])cc21

Procedure:
Three portions of a mixture of concentrated nitric acid (0.6 ml. each portion) and concentrated sulfuric acid (0.66 ml. each portion) were added to a mixture of 3-(2,4-bis(dimethylamino)phenyl)-3-(4-(dimethylamino)phenyl)phthalide (4.17 g.) and concentrated sulfuric acid (20 ml.) with cooling. After each addition the temperature was allowed to rise to room temperature. The resulting mixture was poured onto ice and the resulting mixture was basified, affording 3-(2,4-bis(dimethylamino)phenyl)-3-(4-(dimethylamino)phenyl)-5 or 6-nitrophthalide (I: X = Y4 = (CH3)2N, Y2 = Z4 = Z7 = H, Z5 or Z6 = O2N and the other of Z5 or Z6 = H) or a mixture of both.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C[Al](C)C.[C:17]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)#[N:18].O>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[NH:18])=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: N#Cc1cccnc1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CS(=O)(=O)c1ccc(NC(=N)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline hydrochloride (6 g, 28.8 mmol) in toluene (150 ml) at 0° C., trimethylaluminum (2M solution in toluene, 21.6 ml, 43.2 mmol) was added over 15 minutes. The reaction mixture was warmed to room temperature and stirred for 2.5 hours. A solution of 3-cyanopyridine (6 g, 57.6 mmol) in toluene (150 ml) was added over 10 minutes and the reaction mixture was heated to 90-95° C. After 24 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue was washed with a mixture of methylene chloride/methanol and later methanol. The combined filtrates were concentrated and the resulting yellowish solid was stirred with ethyl acetate (1000 ml) and filtered. The pale yellow amidine (4.5 g, 34%) was used in the next reaction without further purification: mp (DSC) 265° C. Anal Calc'd. for C13H14N3SO2Cl.0.5 H2O: C, 48.67, H, 4.71, N, 13.10. Found: C, 48.34, H, 4.26, N, 12.77.
Reaction SMILES: Br[C:2]1[NH:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]=1[CH3:13].C(C1[C:21]([CH3:22])=[C:20](Br)[NH:19][C:18]=1[CH3:24])(=O)C>>[CH3:7][C:5]1[NH:6][C:2]([C:22]2[CH:24]=[CH:18][N:19]=[CH:20][CH:21]=2)=[C:3]([CH3:13])[C:4]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CC(=O)c1c(C)[nH]c(Br)c1C
Reactant: CCOC(=O)c1c(C)[nH]c(Br)c1C
Product: CCOC(=O)c1c(C)[nH]c(-c2ccncc2)c1C

Procedure:
The title compound was prepared according to the procedure of Example 45 (Method C) using ethyl 5-bromo-2,4-dimetylpyrrole-3-carboxylate (Cordell, G. A, J. Org. Chem., 1975, 40, 3161) instead of 3-acetyl-5-bromo-2,4-dimethyl-1H-pyrrole in step 2.
Reaction SMILES: [N:1]1([CH2:7][C:8](=[CH2:12])[C:9]([OH:11])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(OC(Cl)=O)C(C)C.CN1CCOCC1.[Br:28][C:29]1[CH:30]=[C:31]([NH:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[C:43]([NH2:46])[CH:44]=3)[N:39]=[CH:38][N:37]=2)[CH:32]=[CH:33][CH:34]=1>O1CCCC1.N1C=CC=CC=1.C(OCC)(=O)C>[Br:28][C:29]1[CH:30]=[C:31]([NH:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[C:43]([NH:46][C:9](=[O:11])[C:8]([CH2:7][N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[CH2:12])[CH:44]=3)[N:39]=[CH:38][N:37]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: C=C(CN1CCOCC1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=C(CN1CCOCC1)C(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reaction time: 0.03 h

Procedure:
A tetrahydrofuran solution of 2.06 g (0.012 moles) of 2-Morpholin-4-ylmethyl-acrylic acid in 25 mL of tetrahydrofuran was cooled in an ice bath, and 1.56 mL (1.64 g; 0.012 mole) of isobutylchloroformate was added, giving a precipitate. This was followed by 1.32 mL (1.22 g; 0.012 mole) of N-methylmorpholine. After 2 minutes, 3.15 g (0.01 mole) of N-(3-bromophenyl)-4,6-quinazolindiamine in 25 mL of pyridine was added. Cooling and stirring were continued for 1 ½ hours. Then the reaction was poured onto ice and 25 mL of ethyl acetate. The resulting mixture was extracted with 3 portions of ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over sodium sulfate, and taken to an oil in vacuo. This was washed with water and chromatographed on silica gel. The column was eluted with a gradient ranging from 1:1 ethyl acetate hexanes to 1:19 methanol ethyl acetate. The fifth fraction contained 0.733 g (15%) of the desired product Mass Spectrum (m/e) M+H 235.5.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:17](=[O:27])[CH2:18][NH:19][C:20](OC(C)(C)C)=[O:21])[CH:7]2[CH2:12]C(OC)=O.BrC1C=CC=C2C=1CCNC2CC(OC)=O.C(NCC(O)=O)(OC(C)(C)C)=O.C(N(CC)CC)C.Cl>CCOC(C)=O.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:17](=[O:27])[CH2:18][NH:19][C:20](=[O:21])[CH:12]=[C:7]12
Reactant: COC(=O)CC1c2cccc(Br)c2CCN1C(=O)CNC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: COC(=O)CC1NCCc2c(Br)cccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C1C=C2c3cccc(Br)c3CCN2C(=O)CN1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
methyl 2-(5-bromo-2-(2-((tert-butoxycarbonyl)amino)acetyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate. To a stirred solution of methyl 2-(5-bromo-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (76 g, 267 mmol), Boc-glycine (51.5 g, 294 mmol) and triethylamine (74.6 mL, 535 mmol) in AcOEt (1350 mL), T3P (191 mL, 321 mmol, 50% m/m in AcOEt) was added and the solution was stirred at RT for 90 min. 0.2N aqueous HCl (400 mL) was added and the reaction mixture was stirred for 5 min. The organic layer was separated and washed with 0.2N aqueous HCl (1×250 mL), saturated aqueous NaHCO3 (2×250 mL) and brine (1×250 mL). The combined organic layers were dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was dried under high vacuo overnight to yield the title compound as white foam (113 g) which was used without further purification. UPLC-MS: MS 441.2/443.2 (M+H+); UPLC rt 1.12 min.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][S:7][C:6](=[O:9])[C@@H:5]2[CH2:10][CH2:11][CH2:12][N:4]2[C:3]1=[O:13].CN(C)C=[O:17]>[OH-].[Na+]>[SH:7][CH2:8][CH:2]([CH3:1])[C:3]([N:4]1[CH2:12][CH2:11][CH2:10][C@H:5]1[C:6]([OH:17])=[O:9])=[O:13]
Reactant: CC1CSC(=O)[C@@H]2CCCN2C1=O
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Product: CC(CS)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (4RS-9aS)-hexahydro-4-methyl-1H,5H-pyrrolo [2,1-c][1,4]thiazepine-1,5-dione (2 g) in dimethylformamide (100 ml), normal sodium hydroxide (20 ml) is added. The mixture is stirred for four hours at room temperature under argon. The solvent is removed in vacuo, the residue is dissolved in ethyl acetate and washed with 10% potassium bisulfate and water. The organic layer is dried and concentrated to yield the title compound.
Reaction SMILES: B.[CH2:2]([C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Cl>O1CCCC1>[CH2:2]([C:12]1[CH:13]=[CH:14][C:15]([CH2:16][OH:17])=[CH:19][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCc1ccc(C(=O)O)cc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCc1ccc(CO)cc1

Procedure:
To 69.5 ml. of 1 molar borane in tetrahydrofuran chilled in an ice bath is added dropwise over 40 minutes a solution of 17.2 g. of p-decylbenzoic acid in 150 ml. of dry tetrahydrofuran. The mixture is refluxed for 3.5 hours, chilled, 5 ml. of concentrated hydrochloric acid is added and the mixture poured onto ice. The mixture is filtered and the solid washed with water to give white crystals.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[CH:22][N+:23]([O-])=O)=[CH:17][C:16]=1[O:26][CH3:27])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>O1CCCC1>[CH3:27][O:26][C:16]1[CH:17]=[C:18]([CH2:21][CH2:22][NH2:23])[CH:19]=[CH:20][C:15]=1[O:14][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COc1cc(C=C[N+](=O)[O-])ccc1OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(CCN)ccc1OCc1ccccc1
Reaction time: 1.5 h
Yield: 89.1 %

Procedure:
6.78 g (178.8 mmol) of lithium aluminum hydride and 200 ml of anhydrous tetrahydrofuran were mixed and an anhydrous tetrahydrofuran solution of 17.0 g (59.6 mmol) of 1-benzyloxy-2-methoxy-4-(2-nitrovinyl)benzene was added dropwise thereto over about 90 minutes under vigorous stirring. The mixture was refluxed for 2 hours by heating, and then cooled and aqueous sodium hydroxide solution was added to the mixture. The precipitates were filtered off with celite-precoated glass filter and the solvent was distilled off from the filtrate under reduced pressure. The residue was extracted with ethyl acetate, washed with saturated brine, dried over potassium carbonate and the solvent was distilled off under reduced pressure to give 13.67 g of crude 2-(3-methoxy-4-benzyloxyphenyl)ethylamine.
Reaction SMILES: Cl.[C:2]([OH:14])(=[O:13])/[CH:3]=[CH:4]/[C:5]1[CH:12]=[CH:11][C:9]([OH:10])=[C:7]([OH:8])[CH:6]=1>C(O)CCC>[CH2:2]([O:13][C:2](=[O:14])/[CH:3]=[CH:4]/[C:5]1[CH:12]=[CH:11][C:9]([OH:10])=[C:7]([OH:8])[CH:6]=1)[CH2:3][CH2:4][CH3:5]
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Agent: Cl
Solvent: CCCCO
Product: CCCCOC(=O)/C=C/c1ccc(O)c(O)c1
Reaction time: 3 h
Yield: 106.8 %

Procedure:
To 50 ml of butanol into which hydrogen chloride gas was introduced beforehand for about 10 minutes, was added 2 g of caffeic acid. The resulting mixture was heated at 90° to 100° C. and stirred for 3 hours. The reaction product was concentrated under a reduced pressure, and the residue obtained was purified by means of chromatography and then recrystallized from ether/hexane to give 1.4 g of caffeic acid butyl ester.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=1)(=[O:4])=[O:3].[S:23]1[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29].C([O-])(=O)C.[Na+].O.CC(C)=O>C(O)(=O)C.O>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH:21]=[C:27]2[S:23][C:24](=[O:29])[NH:25][C:26]2=[O:28])=[CH:19][CH:20]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Oc1ccccc1CCOc1ccc(C=O)cc1
Reactant: O=C1CSC(=O)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(C)=O
Product: CS(=O)(=O)Oc1ccccc1CCOc1ccc(C=C2SC(=O)NC2=O)cc1
Reaction time: 0.17 h
Yield: 73.3 %

Procedure:
1.7 g (5.3 mmole) 2-[2-(4-formylphenoxy)ethyl]phenyl methanesulfonate, 0.77 g (6.6 mmole) 2,4-thiazolidinedione and 1.06 g (13.2 mmole) sodium acetate were heated to 130° C. and allowed to stay at 130° C. for 10 minutes. The reaction mixture was taken off the heat and water:acetone (2:1) was added, the formed solid material was stirred with water and acetic acid, the precipitate was collected by filtration and washed with diethyl ether and recrystallized in dichloromethane to give 1.63 g (yield 61%) of 5-(4-[2-(2-methanesulfonyloxyphenyl)ethoxy]benzylidene)thiazolidine-2,4-dione.
Reaction SMILES: [OH:1][C@@H:2]([CH3:6])[C:3]([OH:5])=[O:4].CC(C)([O-])C.[K+].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1>CN(C=O)C>[OH:1][C@@H:2]([CH3:6])[C:3]([O:5][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)=[O:4]
Reactant: COc1ccc(CCl)cc1
Reactant: C[C@H](O)C(=O)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)[C@H](C)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (S)(+)-2 hydroxypropionic acid (9.0 g, 100 mmole) in 100 ml dry DMF was added potassium tert-butoxide (12.34 g, 110 mmole) and the mixture was stirred for one hour at 25° C. 4Methoxybenzyl chloride (18.8 g 120 mmole) was added and the mixture was stirred for six hours at 60° C. The mixture was evaporated under reduced pressure and 250 ml ethyl acatate was added. The organic phase was washed four times with water. The organic phase was dried with sodium sulfate and concentrated in vacuo. Yield: 15.6 g=74%
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH2:5][CH:6]2[NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21][CH2:22][OH:23])=[CH:15][CH:14]=1)(=[O:12])=[O:11]>CCO.[Pd]>[CH3:1][C:2]1([CH3:24])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH2:5][CH:6]2[NH:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=[CH:17][CH:18]=1)(=[O:12])=[O:11]
Reactant: CC1(C)C2CCC(NS(=O)(=O)c3ccc(C#CCCO)cc3)C1C2
Agent: [Pd]
Solvent: CCO
Product: CC1(C)C2CCC(NS(=O)(=O)c3ccc(CCCCO)cc3)C1C2
Reaction time: 16 h
Yield: 104.3 %

Procedure:
A mixture of the product of Step B (0.11 g, 0.3 mmol) and 10% Pd/C (0.06 g) in EtOH (10 ml) was stirred for 16 h under H2. The catalyst was filtered through Celite pad and the filtrate evaporated to dryness to give the title compound (0.11 g, 100%) as creamy gum. 1H-NMR (CDCl3) 7.74 (d, 2H, J=7.89 Hz); 7.29 (d, 2H, J=8.01 Hz); 4.9 (bs, 1H, NH); 3.71-3.65 (m, 2H); 2.92-2.87 (m, 2H); 2.70 (t, 2H, J=7.74 Hz); 2.45-2.30 (m, 1H); 2.25-2.10 (m, 1H); 1.86-1.58 (m, 9H); 1.3-1.1 (m, 2H); 1.08 (s, 3H); 0.83 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:28][O:29][NH2:30])[N:18]([CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[C:14]=2[C:13]2[N:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1>CO>[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:28][O:29][N:30]=[C:2]([CH3:4])[CH3:1])[N:18]([CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[C:14]=2[C:13]2[N:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: CC(C)C(=O)NCCCn1c(CON)nc2c(N)nc3cccnc3c21
Reactant: CC(C)=O
Solvent: CO
Product: CC(C)=NOCc1nc2c(N)nc3cccnc3c2n1CCCNC(=O)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetone (1 mL) was added to a solution of the N-(3-{4-amino-2-[(aminooxy)methyl]-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl}propyl)-2-methylpropanamide from Part I in methanol (10 mL). The reaction mixture was allowed to stir overnight at room temperature. The volatiles were removed under reduced pressure and the residue was purified by chromatography on a HORIZON HPFC system (silica gel, 0-25% CMA in chloroform) to afford 0.495 g of N-{3-[4-amino-2-({[(1-methylethylidene)amino]oxy}methyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]propyl}-2-methylpropanamide as off-white needles, mp 195-197° C.
Reaction SMILES: [CH3:1][CH:2]([C:4](=[O:8])[CH:5]([CH3:7])[CH3:6])[CH3:3].BrBr.[OH:11]C(O)=O>C(Cl)(Cl)Cl>[OH:11][C:2]([CH3:3])([C:4](=[O:8])[CH:5]([CH3:7])[CH3:6])[CH3:1]
Reactant: O=C(O)O
Reactant: CC(C)C(=O)C(C)C
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)C(C)(C)O

Procedure:
To a stirred solution of 28.3 ml. (0.2 mole) 2,4-dimethyl-3-pentanone in 100 ml. chloroform was added dropwise 10.3 ml. (0.2 mole) bromine in 30 ml. of the same solvent. The resulting mixture was stirred for a few minutes, the solvent evaporated in vacuo, the residue taken up in 100 ml. ethanol. Water, 50 ml., and 10 M sodium hydroxide, 50 ml., added. The resulting mixture was stirred at reflux for one hour, diluted with 200 ml. water and extracted with 3×50 ml. ethyl ether. The extracts were dried (MgSO4) evaporated to dryness and the residue distilled to obtain 15.95 g. (61%) of the hydroxy-ketone, b.p. 60°-62° C./18 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[C:24]([O:29][CH2:30][CH3:31])=[N:25][CH:26]=[CH:27][CH:28]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:32][N:33]([CH3:43])[C:34](=[O:42])[CH2:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:39]3[CH2:38][CH2:37][N:36]([CH2:35][C:34]([N:33]([CH3:43])[CH3:32])=[O:42])[CH2:41][CH2:40]3)=[O:21])[C:10]([C:23]3[C:24]([O:29][CH2:30][CH3:31])=[N:25][CH:26]=[CH:27][CH:28]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1ncccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CN(C)C(=O)CN1CCNCC1
Product: CCOc1ncccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)C)CC1

Procedure:
4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-pyridin-3-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 1) was reacted with N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) to give cis-2-{4-[4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-pyridin-3-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N,N-dimethyl-acetamide in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C31H35N6O3Cl2 [(M+H)+] 609.2142, observed 609.2146.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]([CH3:28])[C:14](=[O:27])[C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[CH:9][CH:8]=2)[C:3]1=[O:29].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[CH:21]1([C:18]2[CH:19]=[CH:20][C:15]([C:14]([N:13]([CH3:28])[C:10]3[CH:11]=[CH:12][C:7]([N:4]4[CH2:5][CH2:6][CH:2]([N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)[C:3]4=[O:29])=[CH:8][CH:9]=3)=[O:27])=[CH:16][CH:17]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CN(C(=O)c1ccc(C2CCCCC2)cc1)c1ccc(N2CCC(Br)C2=O)cc1
Reactant: C1COCCN1
Product: CN(C(=O)c1ccc(C2CCCCC2)cc1)c1ccc(N2CCC(N3CCOCC3)C2=O)cc1

Procedure:
N-[4-(3-Bromo-2-oxo-pyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methylbenzamide was reacted with morpholine by method L. This resulted in the product with the molecular weight 461.61 (C28H35N3O3); MS (ESI): 462 (M+H+).
Reaction SMILES: C(NC(N)=N)#N.[CH3:7][NH:8][C:9]([NH:11][CH2:12][CH2:13][S:14][CH2:15][C:16]1[N:17]=[CH:18][NH:19][C:20]=1[CH3:21])=[S:10].[N:22]#[C:23][NH2:24].N#CN.[Pb]>>[C:23]([NH:24][C:9]([NH:8][CH3:7])=[N:11][CH2:12][CH2:13][S:14][CH2:15][C:16]1[N:17]=[CH:18][NH:19][C:20]=1[CH3:21])#[N:22].[CH3:7][NH:8][C:9]([NH:11][CH2:12][CH2:13][S:14][CH2:15][C:16]1[N:17]=[CH:18][NH:19][C:20]=1[CH3:21])=[S:10]
Reactant: N#CN
Agent: CNC(=S)NCCSCc1nc[nH]c1C
Agent: N#CNC(=N)N
Agent: [Pb]
Product: CNC(=NCCSCc1nc[nH]c1C)NC#N

Procedure:
The compounds of Formula I are also useful as intermediates in the production of cyanoguanidine compounds. For example N-methyl-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiourea may be reacted with a heavy metal salt of cyanamide such as lead cyanamide to yield N-cyano-N'-methyl-N"-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]guanidine, or N-methyl-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiourea may be alkylated and the resultant isothiourea treated with a strong base and cyanamide to give N-cyano-N'-methyl-N"-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]guanidine.