Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:12]([C:14]1[CH:19]=[C:18]([O:20]C)[N:17]=[C:16]([N:22]2[CH2:27][CH2:26][CH:25]([N:28]3[C:36]4[C:31](=[N:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:37])[CH2:24][CH2:23]2)[CH:15]=1)=[O:13].Cl.N1C=CC=CC=1>CN(C=O)C>[F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:12]([C:14]1[CH:15]=[C:16]([N:22]2[CH2:27][CH2:26][CH:25]([N:28]3[C:36]4[C:31](=[N:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:37])[CH2:24][CH2:23]2)[NH:17][C:18](=[O:20])[CH:19]=1)=[O:13]
Reactant: COc1cc(C(=O)N2CCc3c2ccc(F)c3F)cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)n1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)[nH]c(=O)c1)N1CCc2c1ccc(F)c2F
Reaction time: 0.12 h

Procedure:
A well stirred mixture of 100 mg (0.197 mmol) 1-[4′-(4,5-difluoro-2,3-dihydro-indole-1-carbonyl)-6′-methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-1,3-dihydro-imidazo[4,5-b]pyridin-2-one and 0.500 g (4.33 mmol) pyridine hydrochloride was kept in a melt for 7 min using a hot air blower. After the reaction had cooled the mixture was dissolved in DMF and purified by preparative HPLC. The product-containing fractions were combined and lyophilised.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:4].[N-:14]=[N+:15]=[N-:16].[Na+]>O1CCCC1.C(O)C.O>[N:14]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:4])=[N+:15]=[N-:16]
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: [N-]=[N+]=NCC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.33 h

Procedure:
To a mixture of 2-bromo-1-(4-nitro-phenyl)-ethanone (2.0 g, 8.2 mmol) in tetrahydrofuran (15 ml) and ethanol (15 ml) was added a solution of sodium azide (586 mg, 9.8 mmol) in water (1.5 ml). After stirring for 20 minutes, the mixture was concentrated under reduced pressure. The residue was treated with saturated aqueous sodium chloride solution (200 ml) and extracted with ethyl acetate (200 ml). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give crude 2-azido-1-(4-nitrophenyl)-ethanone.
Reaction SMILES: [C:1]1([CH:7]([CH3:12])[CH2:8][SiH:9]([Cl:11])[Cl:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]=[CH2:22])=[CH2:14]>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[C:1]1([CH:7]([CH3:12])[CH2:8][Si:9]([C:19]2[CH:18]=[CH:17][C:16]([CH2:21][CH3:22])=[C:15]([CH2:13][CH3:14])[C:20]=2[Si:9]([Cl:10])([Cl:11])[CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH3:12])([Cl:11])[Cl:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=Cc1ccccc1C=C
Reactant: CC(C[SiH](Cl)Cl)c1ccccc1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: CCc1ccc([Si](Cl)(Cl)CC(C)c2ccccc2)c([Si](Cl)(Cl)CC(C)c2ccccc2)c1CC
Yield: 70.4 %

Procedure:
In the same apparatus and procedures as EXAMPLE 1, 18.5 g (0.084 mole) of 3-(phenyl)-1,1-dichloro-1-silabutane and 90 μl of 1% chloroplatinic acid solution in isopropanol were placed and then 5.0 g (0.038 mole) of divinylbenzene was added dropwise for 10 min. The solution was reacted for 6 hours at room temperature under the dry nitrogen atmosphere. Vacuum distillation gave 15.2 g (186°-188° C./0.03 mmHg) of bis{(2-phenylpropyl)dichlorosilyl}diethylbenzene in 70.4% yield.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:14]([NH2:16])=[O:15])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[N:6]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[C:34](F)[CH:33]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.O>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][O:31][C:32]2[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[C:36]([NH:1][C:2]3[S:3][C:4]([C:14](=[O:15])[NH2:16])=[C:5]([C:7]4[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=4)[N:6]=3)[CH:37]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc([N+](=O)[O-])c(F)c2)CC1
Reactant: NC(=O)c1sc(N)nc1-c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc([N+](=O)[O-])c(Nc3nc(-c4cccc(Cl)c4)c(C(N)=O)s3)c2)CC1
Yield: 18.5 %

Procedure:
To a mixture of 0.35 g (1.38 mmole) of 2-amino-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (V.2), 0.59 g (1.66 mmole) of 4-(3-fluoro-4-nitro-phenoxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (IV.23) and 10 mL of dimethylformamide was added 2.24 g (6.90 mmole) of cesium carbonate. The mixture was heated at 70 degrees for 5 hours and then diluted with ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexanes (gradient 0:100-40:60) to give 0.15 g of 4-{3-[5-carbamoyl-4-(3-chloro-phenyl)-thiazole-2-ylamino]-4-nitro-phenoxymethyl}-piperidine-1-carboxylic acid tert-butyl ester (VI.23).
Reaction SMILES: [CH3:1][N:2]([C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[NH2:3].[C:20](Cl)(Cl)=[S:21].C(N(CC)CC)C>O1CCCC1>[CH3:1][N:2]1[C:4](=[O:5])[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20](=[S:21])[NH:3]1
Reactant: S=C(Cl)Cl
Reactant: CN(N)C(=O)Nc1ccccc1Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1[nH]c(=S)n(-c2ccccc2Oc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.54 g of 1-methyl-N-(2-phenoxyphenyl)hydrazinecarboxamide in 50 mL of tetrahydrofuran, cooled in an ice bath, was treated with 0.46 mL of thiophosgene, and then 1.68 mL of triethylamine. A precipitate formed and the mixture was stirred at ambient temperature overnight. The precipitate was removed by filtration and washed with tetrahydrofuran. The combined filtrate and washings were concentrated under reduced pressure to afford 1.8 g of an amber glassy oil. The crude material was used in the next step without further purification. 1H NMR (CDCl3): δ6.8-7.4 (m, 9H), 3.57 (s,3H).
Reaction SMILES: O.C([N:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[C:19]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)=[N:18][N:17]=2)[CH2:11][CH2:10]1)C1C=CC=CC=1>C(O)C.C(O)=O.C(OC(C)C)(C)C.[Pd]>[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20]([C:19]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)=[N:18][N:17]=[C:16]2[NH:15][CH:12]2[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]2)=[CH:21][CH:22]=1
Reactant: COc1ccc(-c2nnc(NC3CCN(Cc4ccccc4)CC3)c3cc(OC)ccc23)cc1
Agent: [Pd]
Solvent: O
Solvent: CCO
Solvent: CC(C)OC(C)C
Product: COc1ccc(-c2nnc(NC3CCNCC3)c3cc(OC)ccc23)cc1
Temperature: 85 °C
Yield: 97 %

Procedure:
1 g of 10% palladium-on-charcoal and 100 mL of water are introduced into a 500 mL three-necked flask. A solution, prepared beforehand, of 13.3 g of N-(1-benzylpiperidin-4-yl)-7-methoxy-4-(4-methoxyphenyl)phthalazin-1-amine (compound 7) in 50 mL of ethanol and 4.4 mL of formic acid is added dropwise over 1 hour, to this mixture with stirring at 85° C. The reaction mixture is stirred at reflux for 2 hours. After cooling to room temperature, the ethanol is evaporated off under reduced pressure. The mixture is then basified to pH 12 with 2N sodium hydroxide solution and is then extracted with dichloromethane. The organic phase is washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The yellow oil obtained is concreted in diisopropyl ether to give a white solid. After filtration and drying under vacuum in the presence of phosphorus pentoxide, 10.29 g of 7-methoxy-4-(4-methoxyphenyl)-N-(piperidin-4-yl)-phthalazin-1-amine are obtained (97% yield).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[CH3:17][N:18]([CH3:26])[CH:19]=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(N(CC)CC)C>O1CCCC1.CN(C)C=O>[CH3:17][N:18]([CH3:26])[CH:19]=[C:20]([C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([F:12])=[C:10]([F:11])[C:2]=1[F:1])[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: O=C(O)c1ccc(F)c(F)c1F
Reactant: CCOC(=O)C=CN(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(=CN(C)C)C(=O)c1ccc(F)c(F)c1F
Yield: 85.7 %

Procedure:
A mixed solution of 2,3,4-trifluorobenzoic acid (10.3 g, 58.5 mmol), thionyl chloride (6.4 ml, 87.8 mmol) and a catalytic amount of dimethylformamide was heated under reflux for 30 minutes. After letting the reaction solution cool, the reaction solution was concentrated under a reduced pressure, toluene (30 ml) was added to the residue, and concentration under a reduced pressure was performed again. The residue obtained was then dissolved in tetrahydrofuran (20 ml), and the resulting solution was added to a tetrahydrofuran (40 ml) solution of ethyl β-dimethylaminoacrylate (9.20 g, 64.3 mmol) and triethylamine (10.2 ml, 73.1 mmol) while stirring and cooling with ice. The reaction mixture was then stirred at room temperature for 1.5 hours and then heated under reflux for 16.5 hours. After letting the reaction solution cool, the precipitated solids were removed by filtration and the filtrate was concentrated under a reduced pressure. The residue was then applied to a silica gel chromatography, and 15.1 g (86%) of the title compound was obtained from an n-hexane:ethyl acetate=3:1 eluate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=1)[O:8][CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])=[O:4]>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1.ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=1)[O:8][CH2:9][C:10]([OH:12])=[O:11])=[O:4]
Reactant: COC(=O)c1cccc(OCC(=O)OC(C)(C)C)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cccc(OCC(=O)O)c1
Yield: 86 %

Procedure:
A solution of t-butyl [3-(methoxycarbonyl)phenoxy]acetate in trifluoroacetic acid (1 kg), anisole (100 mL) and dichloromethane (1 L) was stirred at room temperature for 48 hours. The reaction mixture was concentrated and then the residue was crystallized from diisopropyl ether to obtain the title compound (467 g, 86%) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1([C:13]2[C:21]3[C:16](=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[CH3:25][O-].[Na+].IC>CN(C)C=O.CCOCC>[CH2:1]([C:3]1([C:13]2[C:21]3[C:16](=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:25])[CH:14]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1(c2c[nH]c3c([N+](=O)[O-])cccc23)CCc2cc(F)ccc21
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CI
Product: CCC1(c2cn(C)c3c([N+](=O)[O-])cccc23)CCc2cc(F)ccc21
Yield: 95.6 %

Procedure:
Combine 3-(1-ethyl-5-fluoro-indan-1-yl)-7-nitro-1H-indole (0.33 g, 1.02 mmol), sodium methoxide (110 mg, 2.04 mmol), and iodomethane (0.10 ml, 1.53 mmol) in dimethylformamide (5 ml) and stir at room temperature under nitrogen overnight. Dilute with ether, wash with water (2×), dry over sodium sulfate, filter, and concentrate to obtain the title compound as a yellow amorphous solid (0.33 g, 94%). LC-MS m/z 339.1 (M++1).
Reaction SMILES: [F:1][CH:2]([F:15])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([OH:14])=O)[N:4]=1.C(Cl)(=O)C(Cl)=O.[Cl-].[F:23][C:24]1[C:29]([OH:30])=[CH:28][CH:27]=[C:26]([F:31])[C:25]=1[CH:32]1[O:36][N:35]=[C:34]([C:37]2[N:38]=[C:39]([CH:42]3[CH2:47][CH2:46][NH2+:45][CH2:44][CH2:43]3)[S:40][CH:41]=2)[CH2:33]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl.CN(C)C=O>[F:15][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([CH:8]([F:9])[F:10])[N:5]([CH2:11][C:12]([N:45]2[CH2:46][CH2:47][CH:42]([C:39]3[S:40][CH:41]=[C:37]([C:34]4[CH2:33][CH:32]([C:25]5[C:26]([F:31])=[CH:27][CH:28]=[C:29]([OH:30])[C:24]=5[F:23])[O:36][N:35]=4)[N:38]=3)[CH2:43][CH2:44]2)=[O:14])[N:4]=1
Reactant: Oc1ccc(F)c(C2CC(c3csc(C4CC[NH2+]CC4)n3)=NO2)c1F
Reactant: O=C(O)Cn1nc(C(F)F)cc1C(F)F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cn1nc(C(F)F)cc1C(F)F)N1CCC(c2nc(C3=NOC(c4c(F)ccc(O)c4F)C3)cs2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [3,5-bis-(difluoromethyl)-1H-pyrazol-1-yl]acetic acid (2 g) in dichloromethane (40 ml) are added, at 0° C., oxalyl chloride (3.273 g) and one drop of N,N-dimethylformamide. The reaction mixture is stirred at room temperature for 2 hours. The solvent and the excess reagent are removed under reduced pressure. The solid residue is again dissolved in dichloromethane (15 ml) and, at 0° C., added dropwise to a solution of 4-{4-[5-(2,6-difluoro-3-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidinium chloride (compound A) and triethylamine (5.0 eq.) in dichloromethane (100 ml). The reaction mixture is stirred at room temperature overnight. Then it is admixed with concentrated sodium hydrogencarbonate solution, and the aqueous phase is removed and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated. Purification by column chromatography gives 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2,6-difluoro-3-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone (1.818 g).
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:19]([OH:21])=[O:20])[CH2:3][CH2:4][CH2:5][NH:6]C(=C1C(=O)CC(C)(C)CC1=O)C.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[NH2:1][C@H:2]([C:19]([OH:21])=[O:20])[CH2:3][CH2:4][CH2:5][NH2:6]
Reactant: CC(NCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)=C1C(=O)CC(C)(C)CC1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: NCCC[C@H](N)C(=O)O

Procedure:
Fmoc-Orn(Dde)-OH (386 mg, 0.744 mmol, 4 equiv.), HOBt (114 mg, 0.744 mmol, 4 equiv.) and HBTU (282 mg, 0.744 mmol, 4 equiv.) were dissolved in 2.3 ml DMF. This mixture was let stand at room temperature for 10 min before 0.4 M N-methylmorpholine (in DMF) (3.7 ml, 1.488 mmol, 8 equiv.) was added to it. The resin was treated with this new mixture with gentle rocking for ˜3 h. After the solution was filtered away, the resin was washed three times with DMF (5 ml each time).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([CH:11]([CH3:13])[CH3:12])[O:8][C:9](=O)[C:4]=2[CH:3]=1.[CH3:16][NH2:17]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:14][CH:15]=1)[N:6]=[C:7]([CH:11]([CH3:13])[CH3:12])[N:17]([CH3:16])[C:9]2=[O:8]
Reactant: CC(C)c1nc2ccc(Cl)cc2c(=O)o1
Reactant: CN
Product: CC(C)c1nc2ccc(Cl)cc2c(=O)n1C
Temperature: 90 °C
Yield: 33 %

Procedure:
A mixture of 6-chloro-2-isopropyl-benzo[d][1,3]oxazin-4-one (2.75 g, 12.3 mmol) and methylamine (7.4 mL, 14.8 mmol, 2M solution in MeOH) were heated to 90° C. for 24 hours. The solvent was removed in vacuo and the residue was heated under reduced pressure to 160° C. for 2 hours. The reaction mixture was purified by column chromatography (0-30% ethyl acetate-hexanes) to yield the product (960 mg, 33%). 1H NMR H NMR (400 MHz, CDCl3) δ 8.23 (d, J=2.4 Hz, 1H), 7.65 (dd, J=8.7, 2.4 Hz, 1H), 7.61 (d, J=8.8 Hz, 1H), 3.69 (s, 3H), 3.22 (septet, J=6.7 Hz, 1H), 1.39 (d, J=6.7 Hz, 6H).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[C:24]([O:28][C:29]([NH:31][C:32]([CH3:39])([CH3:38])[CH:33]=[CH:34][C:35]([OH:37])=O)=[O:30])([CH3:27])([CH3:26])[CH3:25].Cl.[NH2:41][C@H:42]([CH2:60][C:61]1[CH:70]=[CH:69][C:68]2[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=2)[CH:62]=1)[C:43]([NH:45][C@@H:46]([C:54]1[O:58][N:57]=[C:56]([CH3:59])[N:55]=1)[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:44].C(N(CC)CC)C>CN(C)C=O>[C:24]([O:28][C:29](=[O:30])[NH:31][C:32]([CH3:39])([CH3:38])[CH:33]=[CH:34][C:35](=[O:37])[NH:41][C@@H:42]([C:43](=[O:44])[NH:45][C@@H:46]([C:54]1[O:58][N:57]=[C:56]([CH3:59])[N:55]=1)[CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[CH2:60][C:61]1[CH:70]=[CH:69][C:68]2[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=2)[CH:62]=1)([CH3:25])([CH3:26])[CH3:27]
Reactant: CC(C)(C=CC(=O)O)NC(=O)OC(C)(C)C
Reactant: Cc1noc([C@@H](Cc2ccccc2)NC(=O)[C@H](N)Cc2ccc3ccccc3c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1noc([C@@H](Cc2ccccc2)NC(=O)[C@@H](Cc2ccc3ccccc3c2)NC(=O)C=CC(C)(C)NC(=O)OC(C)(C)C)n1
Yield: 94.3 %

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.42 g, 2.18 mmol) and 1-hydroxybenzotriazole monohydrate (0.33 g, 2.18 mmol) were added to a solution of 4-tertbutoxycarbonylamino-4-methylpent-2-enoic acid (0.50 g, 2.18 mmol) in N,N-dimethylformamide (7 ml). After 30 min at 20° C. a mixture of (2R)-2-amino-N-[(1R)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-phenylethyl]-3-(2-naphthyl)propionamide hydrochloride (0.68 g, 1.56 mmol) and triethylamine (0.16 g, 1.56 mmol) in N,N-dimethylformamide (8 ml) were added. After 18 h at 20° C. the reaction mixture was poured on ice water (90 ml) and extracted several times with ethyl acetate (total 90 ml). The organic phases were collected and washed with aqueous citric acid (10%, 15 ml), a saturated solution of sodium hydrogencarbonate (3×15 ml) and water (3×15 ml). After drying (magnesium sulfate) the solution was concentrated in vacuo and purified by flash chromatography on silica gel (95 g) using ethyl acetate and heptane (1:1) as eluent to give 0.90 g of {1,1-dimethyl-3-[(1R)-1-((1R)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-phenylethylcarbamoyl)-2-(2-naphthyl)ethylcarbamoyl]allyl}carbamic acid tertbutyl ester.
Reaction SMILES: [CH3:1][C:2]([CH2:9][N+:10]([O-])=O)=[CH:3][CH2:4][O:5][C:6](=[O:8])[CH3:7].N1C=CC=CC=1.P(Cl)(Cl)Cl.Cl>C(Cl)Cl>[CH3:1][C:2]([C:9]#[N:10])=[CH:3][CH2:4][O:5][C:6](=[O:8])[CH3:7]
Reactant: CC(=O)OCC=C(C)C[N+](=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: ClP(Cl)Cl
Product: CC(=O)OCC=C(C)C#N
Reaction time: 1 h

Procedure:
To 500 mg. (0.003 m) of acetic acid(3-methyl-4-nitro-2-buten-1-yl)ester in 10 ml. of pyridine was added, under an atmosphere of nitrogen, 8 ml. of a 10% solution of phosphorous trichloride (0.008 m) in methylene chloride. After standing for 1 hour at room temperature the reaction mixture was poured, under cooling, into 3N HCl. The reaction mixture was then extracted with ether, washed with saturated sodium chloride solution and dried over magnesium sulfate. The solvent was then evaporated after filtration of the drying agent. The acetic acid (3-methyl-3-cyano-2-propen-1-yl)-ester obtained as a yellow oily residue was purified via vacuum distillation, b.p. 63°/0.05 mmHg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[S:15][C@@H:16]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C@@H:17]([OH:21])[C:18](=[O:20])[NH:19][C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl.[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36]Cl.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[C:14]2[S:15][C@@H:16]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[C@@H:17]([OH:21])[C:18](=[O:20])[N:19]([CH2:36][CH2:35][N:34]([CH3:38])[CH3:33])[C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc([C@@H]2Sc3c(cccc3OCc3ccccc3)NC(=O)[C@@H]2O)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc([C@@H]2Sc3c(OCc4ccccc4)cccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Temperature: 22 °C
Reaction time: 0.5 h

Procedure:
To a solution of 751 mg (1.85 mmol) of (+/−)-(2S,3S)-9-(benzyloxy)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one in 7 mL of DMF was added 81 mg (2.03 mmol) of sodium hydride (60% dispersion in mineral oil). The mixture was stirred at 22° C. for 30 minutes. In a separate flask, 408 mg (2.03 mmol) of 2-(dimethylamino)ethylchloride hydrochloride and 81 mg (2,03 mmol) of sodium hydride (60% dispersion in mineral oil), was added to 7 mL of DMF. The mixture was stirred for 30 minutes at 22° C. and then added to the former mixture. The reaction was heated to 45° C. and stirred for 27 hours. A mixture of 1:1 saturated NaHCO3 and water was added to the reaction, and the mixture was extracted with ethyl acetate (3×). The organic layers were combined, washed with brine, dried (Na2SO4), and evaporated. The resulting crude product was purified by flash chromatography on silica gel, eluting first with DCM then gradually increasing to 3.5% methanol/DCM to give (+/−)-(2S,3S)-9-(benzyloxy)-5-(2-(dimethylamino)ethyl)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:26]([NH:28][CH2:29][C@H:30]([OH:45])[CH2:31][N:32]5[CH2:37][CH2:36][N:35]([C:38](OC(C)(C)C)=O)[CH2:34][CH2:33]5)=[O:27])=[C:21]5[C:25]=4[O:24][CH2:23][CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:46])[C:8](=[O:47])[C@H:7]2[CH2:48][CH3:49])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(=O)(O)[O-].[Na+].C1(C)C=CC(S(OC)(=O)=O)=CC=1>ClCCl.O1CCOCC1.O>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:26]([NH:28][CH2:29][C@H:30]([OH:45])[CH2:31][N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)=[O:27])=[C:21]5[C:25]=4[O:24][CH2:23][CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:46])[C:8](=[O:47])[C@H:7]2[CH2:48][CH3:49])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)NC[C@H](O)CN4CCN(C(=O)OC(C)(C)C)CC4)c4c3OCC4)nc2N1C1CCCC1
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)NC[C@H](O)CN4CCN(C)CC4)c4c3OCC4)nc2N1C1CCCC1
Reaction time: 0.5 h
Yield: 29.8 %

Procedure:
Tert-butyl 4-[(2S)-3-[[7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carbonyl]amino]-2-hydroxy-propyl]piperazine-1-carboxylate 7d (580 mg, 0.85 mmol) was dissolved in 50 mL of dichloromethane followed by the addition of 20 mL of a 4 M solution of hydrogen chloride in dioxane. The reaction solution was stirred for 0.5 hours and concentrated under reduced pressure. The resulting residue was dissolved in 40 mL of acetonitrile followed by the addition of sodium bicarbonate (285 mg, 3.40 mmol) and methyl p-toluenesulfonate (316 mg, 1.70 mmol) and stirred for 12 hours. The resulting solution was added with 50 mL of water and extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL×3), dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-N-[(2S)-2-hydroxy-3-(4-methylpiperazin-1-yl)propyl]-2,3-dihydrobenzofuran-4-carboxamide 8 (150 mg, yield: 30.0%) as a white solid.