Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH:24]4[CH2:26][CH2:25]4)=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][C:28]1=[O:32]>>[CH:24]1([C:20]2[CH:21]=[C:22]([CH3:23])[C:17]([N:14]3[CH2:15][CH2:16][N:11]([C:9]([C:5]4[CH:4]=[CH:3][C:2]([N:27]5[CH2:31][CH2:30][CH2:29][C:28]5=[O:32])=[N:7][C:6]=4[CH3:8])=[O:10])[CH2:12][CH2:13]3)=[N:18][CH:19]=2)[CH2:26][CH2:25]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)nc2C)CC1
Reactant: O=C1CCCN1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCC3=O)nc2C)CC1

Procedure:
Using (6-bromo-2-methylpyridin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 249 and pyrrolidin-2-one (41 μL) and by the reaction and treatment in the same manner as in Example 262, the title compound (137 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.BrC1C(=O)C2C(C=1C1C=CC=CC=1)=CC=C(O)C=2.O[CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][S:50](=[O:54])(=[O:53])[CH2:49][CH2:48]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[O:53]=[S:50]1(=[O:54])[CH2:51][CH2:52][N:47]([CH2:46][CH2:45][O:18][C:14]2[CH:13]=[C:12]3[C:17]([C:9]([C:4]4[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=4)=[C:10]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:11]3=[O:19])=[CH:16][CH:15]=2)[CH2:48][CH2:49]1
Reactant: O=S1(=O)CCN(CCO)CC1
Reactant: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(O)cc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(OCCN3CCS(=O)(=O)CC3)cc21
Reaction time: 13 h

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 3-(3,5-difluorophenyl)-6-hydroxy-2-(pyridin-3-yl)-1H-inden-1-one obtained in Step 1 of Example 64 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, 4-(2-hydroxyethyl)thiomorpholine-1,1-dioxide (2.0 eq) instead of 4-(2-hydroxyethyl)morpholine, using 2 equivalents of PPh3 and DIAD, and being stirred for 13 h to provide 6-[2-(1,1-dioxothiomorpholin-4-yl)ethoxy]-3-(3,5-difluorophenyl)-2-(pyridin-3-yl)-1H-inden-1-one, which was treated with HCl/dioxane following the same procedure in Step 8 of Example 1 (40% for 2 steps).
Reaction SMILES: [CH:1]1[C:6]([CH:7]=[O:8])=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[CH3:12][Si:13](C#N)([CH3:15])[CH3:14].[C-:18]#[N:19].[K+].C1OCCOCCOCCOCCOCCOC1>CCOCC.C(=O)(O)[O-].C(Cl)Cl>[CH3:12][Si:13]([CH3:15])([CH3:14])[O:8][CH:7]([C:6]1[CH:1]=[CH:2][C:3]2[O:11][CH2:10][O:9][C:4]=2[CH:5]=1)[C:18]#[N:19]
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: C[Si](C)(C)C#N
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: CCOCC
Product: C[Si](C)(C)OC(C#N)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a nitrogen flushed magnetically stirred 3 L single neck round bottom flask fitted with a nitrogen inlet was charged 285 g (1.9 mol) of piperonal, 200 g (2.0 mol) of trimethylsilylcyanide, 0.2 g of potassium cyanide, 0.2 g of 18-crown-6 and 500 mL of methylene chloride. The mixture was stirred at ambient temperature for 75 min, during which time the reaction exothermed to 35° C. A second charge of 5 g of piperonal was added and the reaction stirred an additional 75 min. The reaction mixture was diluted with ether and 250 mL of saturated sodiuim bicarbonate solution was added. The mixture was stirred for 20 mm before partitioning. The organic layer was washed with another 250 mL portion of saturated sodiuim bicarbonate, twice with brine (300 mL), dried with sodium sulfate, filtered and concentrated leaving 489.6 g (481.4 g theoretical yield) of the title compound as a pale yellow oil. This was used as is without purification in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[H-].[Na+].CN(C)C=O.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:26])=[O:25])[CH:9]=[CH:10][C:3]=12
Reactant: Brc1ccnc2[nH]ccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(c1ccccc1)n1ccc2c(Br)ccnc21
Temperature: 25 °C

Procedure:
4-Bromo-1H-pyrrolo[2,3-b]pyridine (2 g, 10.15 mmol) and sodium hydride (0.406 g, 10.15 mmol) were added to N,N-Dimethylformamide (30 mL) with stirring and under nitrogen. After 15 minutes the reaction was cooled in an ice bath and benzenesulfonyl chloride (1.295 mL, 10.15 mmol) was added to the reaction mixture. The reaction was stirred in the ice bath for 30 min and then allowed to warm up to room temperature. Water (30 mL) was added to the reaction mixture and the precipitate was collected by filtration to afford the title compound as an orange solid: mass (4.8 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Br:13]N1C(=O)CCC1=O>FC(C1C=CC=CC=1)(F)F.C(OCC)(=O)C.CC(N=NC(C#N)(C)C)(C#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][Br:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(Br)ccc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Solvent: FC(F)(F)c1ccccc1
Product: COC(=O)c1cc(Br)ccc1CBr
Temperature: 90 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
To a solution of methyl 5-bromo-2-methylbenzoate (5.27 g) in trifluoromethylbenzene (50.0 mL) were added AIBN (0.04 g) and N-bromosuccinimide (4.50 g), and the mixture was stirred at 90° C. for 4 hr under argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.89 g).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]([CH:9]([CH3:15])[C:10](OCC)=O)=[N:8][C:4]=2[CH:3]=1.[NH2:18][C:19]1[CH:38]=[CH:37][C:22]([C:23]([NH:25][CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH3:36])=[O:24])=[CH:21][C:20]=1[NH:39][CH3:40]>CN1CCCN(C)C1=O>[OH:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]([CH:9]([C:10]3[N:39]([CH3:40])[C:20]4[CH:21]=[C:22]([C:23]([NH:25][CH2:26][CH2:27][O:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[O:35][CH3:36])=[O:24])[CH:37]=[CH:38][C:19]=4[N:18]=3)[CH3:15])=[N:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)C(C)c1nc2cc(O)ccc2[nH]1
Reactant: CNc1cc(C(=O)NCCOc2ccccc2OC)ccc1N
Solvent: CN1CCCN(C)C1=O
Product: COc1ccccc1OCCNC(=O)c1ccc2nc(C(C)c3nc4cc(O)ccc4[nH]3)n(C)c2c1
Temperature: 170 °C
Yield: 13.1 %

Procedure:
A mixture comprising ethyl 2-(5-hydroxy-1H-benzoimidazol-2-yl)propionate (148 mg, 0.63 mmol), 4-amino-N-[2-(2-methoxyphenoxy)ethyl]-3-methylaminobenzamide (200 mg, 0.63 mmol) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone (0.5 mL) was stirred at room temperature until homogeneous, degassed under vacuum and concentrated by heating at 170° C. for 2 hours under a stream of N2. The residue was cooled to room temperature and rinsed with an excess of ethyl ether. The resulting amorphous material was taken up in 50% aqueous acetonitrile and purified by preparative reverse phase HPLC (2-50% CH3CN/H2O) to provide 2-[1-(5-hydroxy-1H-benzoimidazol-2-yl)ethyl]-N-[2-(2-methoxyphenoxy)ethyl]-3-methyl-3H-benzoimidazole-5-carboxamide (40 mg, 13% yield) as a light pink solid; MS (BioIon) C27H27N5O4 m/e calc 485.59; found 486.5 (MH+).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[N:6]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH2:23][CH2:24][CH2:25][CH2:26][OH:27]>O1CCOCC1>[C:17]1([C:5]2[N:6]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]3[C:3]([N:4]=2)=[C:2]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])[N:10]=[CH:9][N:8]=3)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Clc1ncnc2c1nc(-c1ccccc1)n2-c1ccccc1
Reactant: NCCCO
Solvent: C1COCCO1
Product: OCCCNc1ncnc2c1nc(-c1ccccc1)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.3 %

Procedure:
To the solution of 6-chloro-8,9-diphenyl-9H-purine obtained in step 4 of Example 8 (0.67 g, 2.18 mmol) in dioxane was added 3-aminopropan-1-ol (1.66 mL, 21.8 mmol) at room temperature and stirred for 4 hours at room temperature. The resulting reaction mixture was concentrated under reduced pressure. The residue was diluted with CH2Cl2, and washed with water. The organic layer thus separated was dried over anhydrous MgSO4 and evaporated in vacuo to provide title compound (0.77 g, 98%) as yellow solid.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][C:5]([C:11]1[CH:16]=[C:15]([Br:17])[C:14]([O:18][CH3:19])=[CH:13][C:12]=1[O:20][CH3:21])=[N:6]2.[OH-:22].[K+]>>[Br:17][C:15]1[C:14]([O:18][CH3:19])=[CH:13][C:12]([O:20][CH3:21])=[C:11]([C:5]2[N:4]=[C:3]3[C:7](=[N:8][CH:9]=[N:10][C:2]3=[O:22])[N:6]=2)[CH:16]=1
Reactant: [OH-]
Reactant: COc1cc(OC)c(-c2nc3ncnc(Cl)c3[nH]2)cc1Br
Agent: [K+]
Product: COc1cc(OC)c(C2=NC3=NC=NC(=O)C3=N2)cc1Br

Procedure:
Prepared analogously to Example 16 from 6-chloro-8-(5-bromo-2,4-dimethoxy-phenyl)-purine by reaction with 20% potassium hydroxide solution.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:13]2[C@H:22]3[C:23]([O:25][CH2:26][C@@H:21]3[C@@H:20]([OH:27])[C:19]3[CH:18]=[C:17]4[O:28][CH2:29][O:30][C:16]4=[CH:15][C:14]2=3)=[O:24])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9]C.CSC.CS(O)(=O)=O>FC(F)(F)C(O)=O>[OH:9][C:8]1[C:7]([O:11][CH3:12])=[CH:6][C:5]([CH:13]2[CH:22]3[C:23](=[O:24])[O:25][CH2:26][CH:21]3[CH:20]([OH:27])[C:19]3[C:14]2=[CH:15][C:16]2[O:30][CH2:29][O:28][C:17]=2[CH:18]=3)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc([C@@H]2c3cc4c(cc3[C@H](O)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1OC
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CSC
Product: COc1cc(C2c3cc4c(cc3C(O)C3COC(=O)C23)OCO4)cc(OC)c1O
Yield: 5.7 %

Procedure:
10 g (24 mmol) of podophyllotoxin are dissolved in 60 ml of trifluoroacetic acid. 5.4 ml (72 mmol) of dimethyl sulphide and 47 ml (72 mmol) of methanesulphonic acid are successively added. Stirring is maintained for 9 hours, 5.4 ml (72 mmol) of dimethyl sulphide are again added and stirring is maintained for 9 hours. The medium is run quickly onto ice (600 ml) and extracted with ethyl acetate (3×300 ml). The organic phases are washed with water and then with a NaHCO3 solution to neutrality. After drying over sodium sulphate, filtering and evaporating, 6.3 g of crude demethylation product are obtained. Flash chromatography on silica (elution: CH2Cl2/acetone 9/1) makes it possible to isolate 550 mg of 5-(4-hydroxy-3,5-dimethoxyphenyl)-9-hydroxy-5,8,8a,9-tetrahydro-5aH-furo[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-6-one, that is to say 4′-demethylepipodophyllotoxin of formula (Va). 1.10·g of 5-(3,4-dihydroxy-5-methoxyphenyl)-9-hydroxy-5,8,8a,9-tetrahydro-5aH-furo[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-6-one (Analysed: C20H18O8.0.15H2O; calculated: C %, 61.74; H %, 4.74. found: C %, 61.67; H %, 4.68), and then 1.9 g of 9-hydroxy-5-(3,4,5-trihydroxyphenyl)-5,8,8a,9-tetrahydro-5aH-furo[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-6-one are also isolated. The latter compound has a proton NMR spectrum with the following characteristics: 1H NMR (d6-DMSO) δ 8.65 (m, 2H), 7.95 (m, 1H), 6.71 (s, 1H, H5), 6.47 (s, 1H, H8), 5.98 (d, 2H, J=2 Hz, OCH2O), 5.93 (s, 2H, H2′, H6′), 4.68 (d, 1H, J=3.2 Hz, H4), 4.34 (t, 1H, J=8 Hz, H11a), 4.29 (d, 1H, J=5.2 Hz, H1), 4.16 (dd, 1H, J=8 Hz, J′=10 Hz, H11b), 3.17 (dd, 1H, J=5.2 Hz and J′=14 Hz, H2), 2.76 (m, 1H, H3).
Reaction SMILES: [CH2:1]1[O:20][C:4]2([CH2:9][CH2:8][CH:7]([NH:10][C:11]3[C:16]([Cl:17])=[C:15]([CH2:18][CH3:19])[N:14]=[CH:13][N:12]=3)[CH2:6][CH2:5]2)[O:3][CH2:2]1.[CH2:21]([O:23][CH2:24]C(O)CO)[CH3:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:17][C:16]1[C:11]([NH:10][CH:7]2[CH2:6][CH2:5][C:4]3([O:20][CH:1]([CH2:24][O:23][CH2:21][CH3:22])[CH2:2][O:3]3)[CH2:9][CH2:8]2)=[N:12][CH:13]=[N:14][C:15]=1[CH2:18][CH3:19]
Reactant: CCOCC(O)CO
Reactant: CCc1ncnc(NC2CCC3(CC2)OCCO3)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOCC1COC2(CCC(Nc3ncnc(CC)c3Cl)CC2)O1

Procedure:
3.0 g (10 mmol) of 4-(5-chloro-6-ethylpyrimidin-4-ylamino)-cyclohexanone ethylene ketal and 10 ml of 3-ethoxypropane-1,2-diol together with 100 mg of p-toluenesulfonic acid hydrate were refluxed for 8 hours in 10 ml of toluene. The reaction mixture was extracted by stirring with dilute sodium hydroxide solution and water, the organic phase was dried, and the solvent was stripped off in vacuo. The crude product was purified by silica gel chromatography (eluent petroleum ether/ethyl acetate 3:2). This gave 2.0 g (56.3% of theory) of a colorless oil (diastereomer mixture).
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([F:11])[C:5]([F:12])=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:18]O>>[Br:1][C:2]1[C:7]([C:8]([O:10][CH3:18])=[O:9])=[C:6]([F:11])[C:5]([F:12])=[CH:4][CH:3]=1
Reactant: O=C(O)c1c(Br)ccc(F)c1F
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1c(Br)ccc(F)c1F
Temperature: 25 °C

Procedure:
A stirred solution of 6-bromo-2,3-difluorobenzoic acid and conc. H2SO4 in MeOH was heated at reflux for 18 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. To the residue was carefully added a satd. aq. NaHCO3 solution. The resulting mixture was extracted with CH2Cl2. The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was dried under high vacuum to afford the title compound. ESI MS (M+H) 251.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:17][CH3:18])=[CH:4][C:5]2[S:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=CN=3)=[N:7][C:6]=2[CH:16]=1.O1CCCC1.[C:24](Cl)(Cl)=[S:25].[CH2:28]([N:30](CC)CC)C>>[N:1]([C:2]1[C:3]([O:17][CH3:18])=[CH:4][C:5]2[S:9][C:8]([C:10]3[CH:28]=[N:30][CH:13]=[CH:14][CH:15]=3)=[N:7][C:6]=2[CH:16]=1)=[C:24]=[S:25]
Reactant: CCN(CC)CC
Reactant: S=C(Cl)Cl
Reactant: COc1cc2sc(-c3ccccn3)nc2cc1N
Solvent: C1CCOC1
Product: COc1cc2sc(-c3cccnc3)nc2cc1N=C=S
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5-Amino-6-methoxy-2-(2-pyridinyl)benzothiazole, 8.3 g, 0.0325 mole, is dissolved in 400 cc of tetrahydrofuran containing 9.5 cc, 0.065 mole of triethylamine. Thiophosgene, 2.5 cc, 0.0325 mole, is added, and the resulting mixture stirred at ambient temperature for 4 hours. The precipitate which forms is filtered and washed with tetrahydrofuran. The filtrate is concentrated to dryness. The residue is adsorbed on a silica gel column and eluted with hexane-ethylacetate to yield 1.8 g of crude product. Recrystallization from MeCN/CHCl3 yields 1.2 g of the title product, m.p. 164°-166°.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:12]([SH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[N+:20]([CH3:23])([O-:22])=[O:21].C(N)CN>C(#N)C>[CH2:12]([S:19][C:8]1([CH2:23][N+:20]([O-:22])=[O:21])[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: SCc1ccccc1
Reactant: C[N+](=O)[O-]
Solvent: CC#N
Solvent: NCCN
Product: O=[N+]([O-])CC1(SCc2ccccc2)CCC2(CC1)OCCO2
Yield: 72 %

Procedure:
A mixture of 1,4-dioxaspiro[4.5]decan-8-one (6.00 g), benzylmercaptan (5.00 mL), nitromethane (20 mL), ethylenediamine (2.83 mL) and acetonitrile (25 mL) was heated under reflux for 3 hr. The reaction mixture was concentrated, and the obtained residue was subjected to silica gel column chromatography to give the title compound (8.96 g, yield 72%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio). melting point 121-122° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([NH:32][C@@H:33]([CH3:41])[C:34]([O:36]C(C)(C)C)=[O:35])=[O:31])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.Cl.O1CCOCC1>>[CH3:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([NH:32][C@@H:33]([CH3:41])[C:34]([OH:36])=[O:35])=[O:31])=[CH:24][CH:23]=2)=[CH:20][CH:21]=1
Reactant: C[C@H](NC(=O)CCc1ccc(-c2ccc(CCN3CCC[C@H]3C)cc2)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)CCc1ccc(-c2ccc(CCN3CCC[C@H]3C)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To (S)-tert-butyl 2-(3-(4′-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)propanamido)propanoate 2,2,2-trifluoroacetate (4.4 mg, 7.60 mol) was added 4M hydrogen chloride in dioxane (0.665 mL, 2.66 mmol). The reaction was stirred at room temperature for 4 h. The mixture was concentrated to give the title compound. LCMS m/z=409.4 [M+H]+.
Reaction SMILES: [OH-].[Na+].S(O)(O)(=O)=O.[CH3:8][S:9][C:10](=[NH:12])[NH2:11].CC(OC)(C)C.C1COCC1.[NH2:24][C:25]1[C:26]([C:33](OC(C)=CC(=O)NC(C)(CC)C)=[O:34])=[N:27][C:28]([Br:32])=[C:29]([NH2:31])[N:30]=1>O>[NH2:24][C:25]1[C:26]([C:33]([NH:12][C:10]([S:9][CH3:8])=[NH:11])=[O:34])=[N:27][C:28]([Br:32])=[C:29]([NH2:31])[N:30]=1
Reactant: CSC(=N)N
Reactant: CCC(C)(C)NC(=O)C=C(C)OC(=O)c1nc(Br)c(N)nc1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: O
Product: CSC(=N)NC(=O)c1nc(Br)c(N)nc1N

Procedure:
To NaOH (1 mol/l in water; 30 mL; 30 mmol) is added S-methylisothiourea sulfate (5.42 g; 19.5 mmol. The mixture is stirred until complete solution is achieved. TBME/THF (1:1; 100 mL) and then 1-(2-methyl-2-butyl-carbamoyl)prop-1-en-2-yl 3,5-diamino-6-bromopyrazine-2-carboxylate (Intermediate B.62; 7.52 g; 19.5 mmol) are added and the mixture is stirred at r.t. over night, then water (100 mL) is added. The precipitate formed is filtered off with suction, washed with THF/water (1:2) and then dried at 50° C. to yield the title compound.
Reaction SMILES: [C:1]1([CH:7]([N:9]2[C:13]([C:14]([NH2:16])=O)=[CH:12][N:11]=[CH:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]1([CH:7]([N:9]2[C:13]([C:14]#[N:16])=[CH:12][N:11]=[CH:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(c1ccccc1)n1cncc1C(N)=O
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(c1ccccc1)n1cncc1C#N
Temperature: 25 °C

Procedure:
To a stirred and cooled (-10° C.) solution of 3.7 parts of (-)-1-(1-phenylethyl)-1H-imidazole-5-carboxamide in 50 parts of pyridine are added dropwise, during a 15 minute period, 3.4 parts of phosphoryl chloride. The mixture is allowed to reach room temperature; then heated in a boiling water-bath for 1.5 hrs. The reaction mixture is cooled to room temperature and poured onto 250 parts of ice-water. The precipitated product is filtered off, washed with water and dissolved, in trichloromethane. The solution is dried, filtered and evaporated. The solid residue is crystallized from a mixture of 2,2'-oxybispropane and ethanol, yielding (-)-1-(1-phenylethyl)-1H-imidazole-5-carbonitrile; m.p. 128.7° C.; [α] = -40.23° (c = 1% CH3OH).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[O:19]1[CH:23]=[N:22][N:21]=[C:20]1[C:24]([OH:28])([C:26]#[CH:27])[CH3:25]>>[OH:28][C:24]([C:20]1[O:19][CH:23]=[N:22][N:21]=1)([CH3:25])[C:26]#[C:27][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Reactant: C#CC(C)(O)c1nnco1
Product: CC(O)(C#Cc1ccc2c(c1)-c1nc(C(N)=O)cn1CCO2)c1nnco1
Yield: 3 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(1,3,4-oxadiazol-2-yl)but-3-yn-2-ol to give the titled compound as an off-white solid (3.1 mg, 3%).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][CH2:7][C@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([F:23])[CH:22]=2)[N:19](CC2CC2)[C:18](=[O:28])[CH2:17]3)[CH2:9]1.C(N([CH:35]([CH3:37])[CH3:36])CC)(C)C>ClCCl>[CH3:5][O:4][C:2](=[O:3])[NH:6][CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([F:23])[CH:22]=2)[N:19]([CH:35]2[CH2:37][CH2:36]2)[C:18](=[O:28])[CH2:17]3)[CH2:9]1
Reactant: NC[C@@H]1CN(c2cc(F)c3c(c2)CC(=O)N3CC2CC2)C(=O)O1
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)Cl
Solvent: ClCCl
Product: COC(=O)NC[C@H]1CN(c2cc(F)c3c(c2)CC(=O)N3C2CC2)C(=O)O1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methyl chloroformate (0.070 ml, 0.858 mmol) is added dropwise to (R)-5-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-1-cyclopropylmethyl-7-fluoro-1,3-dihydro-indol-2-one (0.300 g, 0.709 mmol) and diisopropylethylamine (0.37 ml, 2.13 mmol) in dichloromethane (15 ml) at 0° C. The reaction is stirred at 0° C. for 30 minutes and then allowed to warm at room temperature. The reaction mixture is diluted with dichloromethane, washed with water and brine, dried (Na2SO4) and evaporated. The residue is purified by PTLC (10% MeOH/DCM) to give the title compound as an off white solid. HPLC r.t. 4.55 min; 1H NMR (300 MHz, CDCl3) 7.52 (1H), 7.39 (s, H), 7.35 (s, 1H), 4.68-4.66 (m, 1H), 4.09 (t, J=9.0 Hz, 1H), 3.74 (dd, J=9, 6 Hz, 1H), 3.69 (s, 2H), 3.59 (d, J=7.2 Hz, 2H), 3.53 (s, 3H), 3.33 (t, J=5.4 Hz, 2H), 1.26-1.23 (m, 1H), 0.47-0.42 (m, 2H), 0.32-0.29 (m, 2H); MS for C18H20FN3O5 m/z 378.1(M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:35]=[C:34]3[C:29]([CH2:30][CH2:31][C:32](=[O:41])[N:33]3[CH2:36][CH2:37][CH2:38][O:39][CH3:40])=[CH:28][CH:27]=2)=[CH:4][CH:3]=1.C1(C)C=CC(S(O[CH2:52][CH2:53][CH2:54][O:55][CH:56]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[CH3:57])(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:40][O:39][CH2:38][CH2:37][CH2:36][N:33]1[C:34]2[C:29](=[CH:28][CH:27]=[C:26]([CH2:25][O:24][CH:9]3[CH:8]([C:5]4[CH:6]=[CH:7][C:2]([O:1][CH2:52][CH2:53][CH2:54][O:55][CH:56]([C:58]5[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=5)[CH3:57])=[CH:3][CH:4]=4)[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[O:15])[CH2:10]3)[CH:35]=2)[CH2:30][CH2:31][C:32]1=[O:41]
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(O)cc3)cc21
Reactant: Cc1ccc(S(=O)(=O)OCCCOC(C)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCOC(C)c4ccccc4)cc3)cc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
The mixture of 0.200 g of benzyl 4-(4-hydroxyphenyl)-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate, 0.157 g of 3-(1-phenylethoxy)propyl toluene-4-sulphonate and 0.173 g of caesium carbonate in 2.5 ml of acetonitrile is stirred at 80° C. over 2 hours. The reaction mixture is subsequently cooled, poured onto water (25 ml) and extracted with tert-butyl methyl ether (2×25 ml). The organic phases are washed with brine (1×25 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.19 (2:1 EtOAc-heptane); Rt=6.03.