Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]([Cl:15])[C:3]=1[C:4]([OH:6])=O.[NH:16]1[C:24]2[CH:23]=[CH:22][N:21]=[C:20]([NH:25][C:26](=[O:28])[CH3:27])[C:19]=2[CH:18]=[CH:17]1.ClC1C=C(C(=O)NCC)C=C(Cl)C=1C(O)=O>>[C:26]([NH:25][C:20]1[C:19]2[CH:18]=[CH:17][N:16]([C:4]([C:3]3[C:7]([Cl:15])=[CH:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:2]=3[Cl:1])=[O:6])[C:24]=2[CH:23]=[CH:22][N:21]=1)(=[O:28])[CH3:27]
Reactant: COC(=O)c1cc(Cl)c(C(=O)O)c(Cl)c1
Reactant: CC(=O)Nc1nccc2[nH]ccc12
Agent: CCNC(=O)c1cc(Cl)c(C(=O)O)c(Cl)c1
Product: COC(=O)c1cc(Cl)c(C(=O)n2ccc3c(NC(C)=O)nccc32)c(Cl)c1

Procedure:
This was prepared using 2,6-dichloro-4-(methoxycarbonyl)benzoic acid and N-(1H-pyrrolo[3,2-c]pyridin-4-yl)acetamide (Intermediate 29) in an analogous manner.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([F:24])([F:23])([F:22])([F:21])[F:20])=[CH:15][CH:14]=1>>[Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([F:24])([F:20])([F:21])([F:22])[F:23])=[CH:15][CH:14]=1)=[O:9]
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Reactant: Nc1ccc(S(F)(F)(F)(F)F)cc1
Product: O=C(Nc1ccc(S(F)(F)(F)(F)F)cc1)c1cnc(Cl)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 11.2 using 5-bromo-6-chloro-nicotinic acid and 4-aminophenylsulfur pentafluoride to afford an orange solid. HPLC (Condition 4), tR=6.43 min, UPLC-MS (Condition 3), tR=1.27 min, m/z=435.3/437.2 [M+H]+.
Reaction SMILES: C([CH:3]([C:7](Cl)=[O:8])[C:4](Cl)=[O:5])C.[NH2:10][C:11]1[C:15]([CH3:16])=[CH:14][S:13][C:12]=1C(OC)=O.C(N(CC)CC)C>ClCCl>[CH3:16][C:15]1[C:11]2[NH:10][C:7](=[O:8])[CH2:3][C:4](=[O:5])[C:12]=2[S:13][CH:14]=1
Reactant: CCC(C(=O)Cl)C(=O)Cl
Reactant: COC(=O)c1scc(C)c1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1csc2c1NC(=O)CC2=O
Reaction time: 0.5 h
Yield: 48 %

Procedure:
Ethyl malonyl chloride (4.29 g, 28 mmol) was added to a solution of methyl 3-amino-4-methylthiophene-2-carboxylate (4 g, 23 mmol) and triethylamine (4.2 mL, 30 mmol) in dichloromethane (50 mL) and the resulting mixture was stirred for 30 minutes. The reaction mixture was diluted with dichloromethane, washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. To the oily residue was added a freshly prepared ethanolic solution of sodium ethoxyde (0.5 g in 25 mL of EtOH) and the reaction mixture was heated at reflux overnight. The solvent was evaporated under reduced pressure and water (50 mL) was added to the residue, followed by sodium hydroxide (1.5 g). The resulting mixture was heated at reflux overnight, then was cooled and acidified by addition of an aqueous solution of hydrochloric acid (6 M). The solid formed was collected by filtration, washed with water and dried under reduced pressure to afford 2.0 g of 3-methyl-4H-thieno[3,2-b]pyridine-5,7-dione.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH2:18]OS(C1C=CC(C)=CC=1)(=O)=O)[S:4]([C:7]1[C:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:13]=2[CH:14]=[CH:15][CH:16]=1)(=[O:6])=[O:5])[CH3:2].[CH2:30]([NH2:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>ClCCl>[CH2:1]([N:3]([CH2:17][CH2:18][NH:36][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[S:4]([C:7]1[C:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:13]=2[CH:14]=[CH:15][CH:16]=1)(=[O:5])=[O:6])[CH3:2]
Reactant: CCCCCCN
Reactant: CCN(CCOS(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCCCCNCCN(CC)S(=O)(=O)c1cccc2cnccc12
Temperature: 110 °C

Procedure:
To 3.96 g of the thus obtained N-ethyl-N-(2-p-toluenesulfonyloxyethyl)-5-isoquinolinesulfonamide were added 1.25 g of hexylamine, 1.14 g of potassium carbonate and 20 ml of dioxane. The mixture thus obtained was heated in a pressure vessel at 110° C. for 72 hours, and then the dioxane was removed under reduced pressure to obtain a crude product. Then, 60 ml of dichloromethane was added to the crude product, and the mixture thus obtained was washed with 30 ml of water and dried with anhydrous magnesium sulfate. The dichloromethane was removed under reduced pressure to obtain a residue. The residue thus obtained was subjected to purification by silica gel column chromatography (Wacogel C-200, solvent: a 5% methanol solution in chloroform) to obtain 2.50 g of N-ethyl-N-(2-hexylaminoethyl)-5-isoquinolinesulfonamide [Compound (28)]. Compound (28) was analyzed to give the following data.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:10]([Br:11])=[CH:9][C:8]([F:12])=[CH:7][C:6]=1[Br:13].[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([Br:13])=[CH:7][C:8]([F:12])=[C:9]([N+:14]([O-:16])=[O:15])[C:10]=1[Br:11]
Reactant: O=[N+]([O-])O
Reactant: Fc1cc(Br)c(OCCCl)c(Br)c1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(F)cc(Br)c(OCCCl)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
To a solution of 1-(2-chloroethoxy)-2,6-dibromo-4-fluorobenzene (65.8 g, 0.20 mol) in concentrated sulfuric acid (165 mL) maintained at room temperature using a water bath was slowly added a solution of nitric acid in sulfuric acid (10 mL HNO3 in 165 mL H2SO4). The reaction was allowed to stir at room temperature for 1 hour then poured into ice (1.5 L) and extracted with methylene chloride (2×300 mL). The combined organic layers were washed with aqueous sodium bicarbonate (150 mL) and dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum to afford 73.3 g (97.1%) a white crystalline solid: mp 56°-57° C.; MS EI m/e 375/377/379/381; 1H NMR (CDCl3) δ 3.91 (2H, t, J=5.9 Hz), 4.29 (2H, d, J=5.9 Hz), 7.54 (8.1 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH2:10][F:11].CC([O-])(C)C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=[NH:77])(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1>[F:11][CH2:10][CH2:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH2:77]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: FCCOc1ccccc1Br
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: Nc1ccccc1OCCF
Temperature: 120 °C
Yield: 99.9 %

Procedure:
To a solution of the product of Example 126, Step 1 (800 mg, 3.65, mmol) in deoxygenated toluene (15 mL) was added NaOtBu (498 mg, 5.2 mmol), BINAP (364 mg, 0.58 mmol) Pd2(dba)3 (217 mg, 0.24 mmol) and benzophenone imine (0.8 mL, 4.7 mmol). The reaction mixture was heated at 120° C. for 3 h. The crude mixture was then washed with DCM and the aqueous layer was made basic with sat. NaHCO3. The aqueous layer was extracted with DCM and the combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography on silica gel (0-5% MeOH in DCM) to afford the title compound (566 mg, 90%). MS (ESI) mass calcd. C8H10FNO, 155.1. m/z found, 156.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3([CH2:20][CH2:19]3)[CH2:9][N:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:23][C:24]1[CH:39]=[CH:38][C:27]([C:28]([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[O:29])=[CH:26][C:25]=1[F:40].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C>[CH:13]1([N:10]2[CH2:9][C:8]3([CH2:20][CH2:19]3)[C:7](=[O:21])[N:6]([CH3:22])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:39]=[CH:38][C:27]([C:28]([NH:30][CH:31]5[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]5)=[O:29])=[CH:26][C:25]=4[F:40])=[N:12][C:11]2=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCCC2)c2nc(Cl)ncc21
Reactant: CN1CCC(NC(=O)c2ccc(N)c(F)c2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)CC(C)O
Solvent: O
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCCC3)CC3(CC3)C(=O)N4C)c(F)c2)CC1
Temperature: 160 °C

Procedure:
2′-chloro-9′-cyclohexyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 270; 200 mg, 0.62 mmol), 4-amino-3-fluoro-N-(1-methylpiperidin-4-yl)benzamide (Intermediate 65; 157 mg, 0.62 mmol) and p-toluenesulfonic acid monohydrate (296 mg, 1.56 mmol) were suspended in 4-Methyl-2-pentanol (5 mL) and sealed into a microwave tube. The reaction was heated at 160° C. for 30 minutes in the microwave reactor and then allowed to cool to room temperature.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]([NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22](Cl)=[N:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1[Cl:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]1>>[C:1]([NH:9][C:10]1[CH:11]=[C:12]([NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22]([N:27]3[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]3)=[N:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1[Cl:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCNCC1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1)c1ccc(Cl)nc1
Product: O=C(Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1)c1ccc(N2CCC(O)CC2)nc1

Procedure:
N-(3-benzamido-4-chlorophenyl)-6-chloronicotinamide (0.15 mmol) was used in general procedure 3 with piperidin-4-ol (0.77 mmol). The product was purified by RP-HPLC to give N-(3-benzamido-4-chlorophenyl)-6-(4-hydroxypiperidin-1-yl)nicotinamide. MS (Q1) 451.2 (M)+
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]3[N:20]=[C:21]([CH:24]=[CH:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)[O:22][CH:23]=3)=[O:18])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[OH-].[K+].I[CH3:39]>CC(C)=O>[CH3:39][N:16]([C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[N:2]2)=[CH:11][CH:12]=1)[C:17]([C:19]1[N:20]=[C:21]([CH:24]=[CH:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=2)[O:22][CH:23]=1)=[O:18]
Reactant: O=C(Nc1ccc(CCCCn2ccnn2)cc1)c1coc(C=Cc2ccc(C(F)(F)F)cc2)n1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CN(C(=O)c1coc(C=Cc2ccc(C(F)(F)F)cc2)n1)c1ccc(CCCCn2ccnn2)cc1

Procedure:
2-[2-(4-Trifluoromethyl-phenyl)-vinyl]-oxazole-4-carboxylic acid [4-(4-[1,2,3]triazol-1-yl-butyl)-phenyl]-amide (40 mg, 0.083 mmol) is dissolved in acetone (0.6 ml), treated with KOH (17 mg, 0.3 mmol) and iodomethane (17.7 mg, 0.12 mmol) and heated to reflux for 5 min. After cooling the mixture is concentrated, taken up in water (10 ml) and extracted with dichloromethane (2×10 ml). The organic layers are dried over sodium sulfate, concentrated in vacuo and purified by flash column chromatography (ethyl acetate/heptane 9:1) yielding 2-[2-(4-trifluoromethyl-phenyl)-vinyl]-oxazole-4-carboxylic acid methyl-[4-(4-[1,2,3]triazol-1-yl-butyl)-phenyl]-amide 12 as a colorless solid. Yield 30 mg (73%); m.p. 127–129° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:24]3[S:25][C:26]4[C:32]([O:33][CH3:34])=[CH:31][C:30]([CH3:35])=[CH:29][C:27]=4[CH:28]=3)[C:9]([CH2:18][O:19][CH2:20][C:21]([NH2:23])=[O:22])=[C:10]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[N:6]2[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:42](Cl)(=[O:44])[CH3:43]>C1COCC1.ClCCl>[C:42]([N:15]1[CH2:14][CH2:13][N:12]([CH2:11][C:10]2[N:6]3[C:7]([C:2]([NH2:1])=[N:3][CH:4]=[N:5]3)=[C:8]([C:24]3[S:25][C:26]4[C:32]([O:33][CH3:34])=[CH:31][C:30]([CH3:35])=[CH:29][C:27]=4[CH:28]=3)[C:9]=2[CH2:18][O:19][CH2:20][C:21]([NH2:23])=[O:22])[CH2:17][CH2:16]1)(=[O:44])[CH3:43]
Reactant: COc1cc(C)cc2cc(-c3c(COCC(N)=O)c(CN4CCNCC4)n4ncnc(N)c34)sc12
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(C)cc2cc(-c3c(COCC(N)=O)c(CN4CCN(C(C)=O)CC4)n4ncnc(N)c34)sc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of Example 33 (105 mg, 68% purity, 144 μmol) in THF/dichloromethane (1:2.5, 3.9 ml) was treated with sodium carbonate (179 mg, 1.6 mmol) and stirred at rt for 30 min. Acetyl chloride (30 μl, 424 μmol) was added, and the resulting mixture was stirred at rt for 30 min, then quenched with methanol (2 ml) and evaporated. Purification by preparative RP-HPLC (Reprosil C18, gradient 10-95% acetonitrile/0.1% aq. formic acid) afforded 30 mg (85% purity, 34% of th.) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH3:11])[O:10][C:6]=2[C:5]([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])=[CH:4][CH:3]=1.[N+:25]([O-])([OH:27])=[O:26]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]2[C:8]([N+:25]([O-:27])=[O:26])=[C:9]([CH3:11])[O:10][C:6]=2[C:5]([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])=[CH:4][CH:3]=1
Reactant: Cc1cc2c(Cl)ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1oc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)ccc(Cl)c2c1[N+](=O)[O-]
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 67.6 %

Procedure:
0.5 g (1.4 mmol) of 3-(4-chloro-2-methylbenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil was dissolved in 10 ml of concentrated sulfuric acid, and 0.1 g (1.1 mmol) of 60% nitric acid was dropwise added thereto at -20° C. After stirring at -20° C. for 10 minutes, the reaction solution was poured into ice water and extracted with 50 ml of chloroform. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 0.3 g (yield: 53.3%) of the desired product as a pale yellow crystals. Melting point: 174-175° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[Cl:15].Br[CH2:17][CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:21]1(=[O:30])[N:20]([CH2:19][CH2:18][CH2:17][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:4][C:3]=2[Cl:15])[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]12
Reactant: O=C1CCC(c2ccc(O)c(Cl)c2)=NN1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCC(c2ccc(OCCCN3C(=O)c4ccccc4C3=O)c(Cl)c2)=NN1
Reaction time: 0.17 h
Yield: 87.6 %

Procedure:
A mixture of 3.4 g (15.1 mmol) of 6-(4-hydroxy-3-chlorophenyl)-4,5-dihydro-3(2H)-pyridazinone, prepared according to the methods described in Eur. Pat. Appl. 178,189A2, 4.87 g (18.2 mmol) of N-(3-bromopropyl)-phthalimide, and 2.30 g (16.6 mmol) of anhydrous K2CO3 in 80 ml of DMF is heated for 3 hrs at 100° C. The DMF is removed under vacuum and 150 ml of 1:1 EtOAc-H2O is added to the residue and stirred vigorously for 10 min. The solid precipitate is collected by suction filtration, washed with water (2×150 ml), washed with EtOAc (2. 50 ml), and dried under vacuum at 80° C. to give 5.45 g of 6-[4-(3-phthalimidopropyloxy)-3-chlorophenyl]-4,5-dihydro-3(2H)-pyridazinone as a white solid, m.p. 230°-232° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:19]2[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])[O:21][C:20]2=[O:29])[CH:5]=[C:6]([F:18])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:17])[CH2:15][OH:16])[CH2:10][CH2:9]1.C1C=C([O:36]O)C(C(O)=O)=C(C(O)=O)C=1>CO>[F:18][C:6]1[CH:5]=[C:4]([N:19]2[CH2:23][C@@H:22]([CH2:24][NH+:25]([O-:36])[C:26](=[O:28])[CH3:27])[O:21][C:20]2=[O:29])[CH:3]=[C:2]([F:1])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:17])[CH2:15][OH:16])[CH2:10][CH2:9]1
Reactant: O=C(O)c1cccc(OO)c1C(=O)O
Reactant: CC(=O)NC[C@H]1CN(c2cc(F)c(N3CCN(C(=O)CO)CC3)c(F)c2)C(=O)O1
Solvent: CO
Product: CC(=O)[NH+]([O-])C[C@@H]1CN(c2cc(F)c(N3CCN(C(=O)CO)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
(S)-N-[[3-[3,5-Difluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]- acetamide (VIII-A, R1=COCH3, R2=H, X1═X2=F) (0.13 g) is dissolved in 5 mL of methanol. Monoperoxyphthalic acid, magnesium salt hexahydrate (80% pure, 0.2 g) is added and the resulting suspension is stirred at 25° C. for 72 hours. An additional 0.2 g of monoperoxyphthalic acid is added and the reaction is stirred an additional 48 hours. The reaction mixture is filtered and the filtrate is concentrated to afford a light-yellow oil. This material is chromatographed on silica gel using 20% methanol (saturated with ammonia) in chloroform as eluent to afford 55 mg of the N-oxide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8](OC2CCCCO2)[C:9]([C:11]2[O:12][C:13]3[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][C:14]=3[C:15]=2O)=[NH:10])[CH:5]=[CH:6][CH:7]=1.C[OH:30]>>[NH2:21][C:20]1[C:13]2[O:12][C:11]([C:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[N:10][OH:30])=[CH:15][C:14]=2[CH:17]=[CH:18][CH:19]=1
Reactant: CO
Reactant: N=C(c1oc2c(N)cccc2c1O)N(OC1CCCCO1)c1cccc(Cl)c1
Product: Nc1cccc2cc(C(=NO)Nc3cccc(Cl)c3)oc12
Yield: 62 %

Procedure:
To a methanol solution of 32 mg of N-(3-chloro-phenyl)-hydroxy-7-amino-N-(tetrahydro-pyran-2-yloxy)-benzofuran-2-carboxamidine was 200 mg of acidic Dowex resin. The resulted solution was stirred at reflux temperature for 1 h. The reaction mixture was filtered and concentrated under vacuum. The crude product was purified using a chromatotron and eluting with 5-10% methanol/dichloromethane to give 18 mg of 7-amino-N-(3-chloro-phenyl)-N′-hydroxy-benzofuran-2-carboxamidine in 62% yield.
Reaction SMILES: [Si:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:22])[C:19]([OH:21])=O)=[CH:14][C:13]=2[F:23])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[Cl:55][C:56]1[CH:57]=[C:58]([N:62]2[C:66]([CH2:67][NH2:68])=[CH:65][C:64]([C:69]([F:72])([F:71])[F:70])=[N:63]2)[CH:59]=[CH:60][CH:61]=1>C(Cl)Cl>[Si:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:22])[C:19]([NH:68][CH2:67][C:66]3[N:62]([C:58]4[CH:59]=[CH:60][CH:61]=[C:56]([Cl:55])[CH:57]=4)[N:63]=[C:64]([C:69]([F:72])([F:71])[F:70])[CH:65]=3)=[O:21])=[CH:14][C:13]=2[F:23])[CH2:10][CH2:11]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C(=O)O)c1ccc(C2(O[Si](C)(C)C(C)(C)C)CC2)c(F)c1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(=O)NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)c1ccc(C2(O[Si](C)(C)C(C)(C)C)CC2)c(F)c1
Reaction time: 3 h
Yield: 30.9 %

Procedure:
To a stirred solution of 2-(4-(1-(tert-butyldimethylsilyloxy)cyclopropyl)-3-fluorophenyl)propanoic acid (190 mg, 0.56 mmol, 1 eq) in DCM (10 mL) was added DIPEA (0.29 mL, 1.68 mmol, 3 eq) followed by EDC.HCl (128 mg, 0.67 mmol, 1.2 eq) and HOBt (103 mg, 0.67 mmol, 1.2 eq) at RT and stirred for 10 min when (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine (175 mg, 0.56 mmol) was added and the mixture stirred for 3 h. After completion of the reaction the reaction mixture was washed with H2O (15 mL), brine (10 mL), dried (Na2SO4) and the solvents evaporated. The crude product was purified by CC using EtOAc/PE (3:7) to get 2-(4-(1-(tert-butyldimethylsilyloxy)-cyclopropyl)-3-fluorophenyl)-N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)propanamide (103 mg; 31%) as off white solid (TLC system: EtOAc/PE (3:7) Rf: 0.5).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:38]([CH3:39])=[CH:37][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:36]=[CH:35][C:28]5[N:29]([CH3:34])[C:30](=[O:33])[N:31]([CH3:32])[C:27]=5[CH:26]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1OS(C(F)(F)F)(=O)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[Cl:48][C:49]1[CH:54]=[CH:53][C:52](B(O)O)=[CH:51][CH:50]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[C:1]([O:5][C@@H:6]([C:12]1[C:38]([CH3:39])=[CH:37][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:36]=[CH:35][C:28]5[N:29]([CH3:34])[C:30](=[O:33])[N:31]([CH3:32])[C:27]=5[CH:26]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:52]1[CH:53]=[CH:54][C:49]([Cl:48])=[CH:50][CH:51]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5c(c4)n(C)c(=O)n5C)c3)sc2c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccc(Cl)cc1
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: [K+]
Solvent: COCCOC
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5c(c4)n(C)c(=O)n5C)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(2-(2-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)pyridin-4-yl)-5-methyl-7-(trifluoromethylsulfonyloxy)benzo[d]thiazol-6-yl)acetate (15.3 mg, 0.022 mmol), 4-chlorophenylboronic acid (4.0 mg, 0.026 mmol) and K2CO3 (9.0 mg, 0.066 mmol) in DME (0.5 mL) was added Pd(PPh3)4 (2.0 mg, 1.73×10−3 mmol). The reaction was degassed for 5 minutes with N2 and then heated at 120° C. for 6 h. After cooling, the reaction mixture was diluted with EtOAc, extracted with H2O, brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C36H36ClN4O4S: 655.2; found: 655.3.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[N:4]=[C:3]1[CH2:8]O.Cl.[NH2:11][CH2:12][CH2:13][SH:14].C(O)(C)C.CO.[BrH:21]>>[BrH:21].[BrH:21].[CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[N:4]=[C:3]1[CH2:8][S:14][CH2:13][CH2:12][NH2:11]
Reactant: Cc1cn(C)c(CO)n1
Reactant: NCCS
Agent: Br
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: Cc1cn(C)c(CSCCN)n1

Procedure:
The reaction of 1,4-dimethyl-2-hydroxymethylimidazole (2.5 g.) with cysteamine hydrochloride (2.5 g.) in aqueous hydrobromic acid by the method described in Example 1 (i) (a) gave 1,4-dimethyl-2-[(2-aminoethyl)thiomethyl]imidazole dihydrobromide (6.2 g.), m.p. 161°-163° (from isopropyl alcohol-methanol).
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:21])=[C:7]2[C:15](=[C:16]([CH3:19])[C:17]=1[CH3:18])[O:14][C:10]1([CH2:13][CH2:12][CH2:11]1)[CH2:9][C:8]2=[O:20])(=O)C.C[Si]([C:26]#[N:27])(C)C.C1COCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOC(C)=O>[NH2:27][CH2:26][C:8]1([OH:20])[C:7]2[C:15](=[C:16]([CH3:19])[C:17]([CH3:18])=[C:5]([OH:4])[C:6]=2[CH3:21])[O:14][C:10]2([CH2:11][CH2:12][CH2:13]2)[CH2:9]1
Reactant: C[Si](C)(C)C#N
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)C(=O)CC1(CCC1)O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O)C(O)(CN)CC1(CCC1)O2
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 5,7,8-trimethyl-4-oxo-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-yl acetate (2 g), Znl2 (100 mg) and trimethylsilyl cyanide (4 mL) was stirred at 70° C. for 2 h. A homogeneous solution was obtained. The solution was cooled down to room temperature, and THF (30 mL) was added, followed by 1 g of lithium aluminum hydride. After stirring at 60° C. for 3 h, the solution was cooled down and EtOAc was added to destroy excess lithium aluminum hydride. The mixture was poured into water and extracted with EtOAc. The EtOAc was washed with water and dried. After evaporation a white solid was obtained (1 g), which was washed with DCM to give 4-(aminomethyl)-5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutane]-4,6-diol. 1H-NMR (300 MHz, CDCl3+CD3OD): δ=2.85 (AB, J=13.44 Hz, 2H), 2.36 (s, 2H), 2.35-1.60 (m, 6H), 2.11 (s, 9H) ppm. 13C-NMR (75 MHz, CDCl3+CD3OD) δ=146.82, 145.54, 124.91, 123.75, 121.01, 120.48, 76.49, 75.64, 50.07, 44.97, 34.46, 32.36, 13.75, 13.31, 12.50, 12.22 ppm. MS: (m/z)=260 (M+−OH).