Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH2:19][OH:20])[CH2:15][C@H:14]1[CH2:13][S:12][C:11]([NH:21][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[N:10]2.O.C[N+]1([O-])CC[O:35]CC1.CC(O)C>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:22]([NH:21][C:11]1[S:12][CH2:13][C@@H:14]2[CH2:15][C@H:16]([C:19]([OH:35])=[O:20])[O:17][CH2:18][C@:9]2([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[N:10]=1)(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CO)C[C@H]2CS1)c1ccccc1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: O
Solvent: CC#N
Solvent: CC(C)O
Product: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](C(=O)O)C[C@H]2CS1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Tetrapropylammonium perruthenate (1.09 g, 3.10 mmol) was added to a mixture of N-[(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(hydroxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (P1) (13.0 g, 31.1 mmol) and 4-methylmorpholine N-oxide monohydrate (25.2 g, 186 mmol) in acetonitrile (207 mL), and the reaction mixture was stirred for 90 minutes at room temperature. After addition of 2-propanol (100 mL), it was stirred for an additional 2 hours and then concentrated in vacuo. The residue was partitioned between ethyl acetate and 0.5 M aqueous sodium hydroxide solution. The organic layer was extracted twice with 0.5 M aqueous sodium hydroxide solution, and the combined aqueous layers were acidified to a pH of approximately 1 with 2 M aqueous hydrochloric acid, then extracted three times with ethyl acetate. The combined ethyl acetate layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure; the residue was dissolved in dichloromethane, washed with water and with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via chromatography on silica gel (Gradient: 0% to 20% methanol in dichloromethane) provided the product as a reddish solid. Yield: 12.36 g, 28.58 mmol, 92%. LCMS m/z 433.2 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 8.09-8.13 (m, 2H), 7.52-7.57 (m, 1H), 7.43-7.51 (m, 3H), 7.03-7.11 (m, 2H), 4.35 (dd, J=11.2, 3.4 Hz, 1H), 4.19 (dd, J=12.0, 1.4 Hz, 1H), 3.97 (d, J=12.1 Hz, 1H), 3.20-3.27 (m, 1H), 2.96 (dd, half of ABX pattern, J=13.1, 4.0 Hz, 1H), 2.78 (dd, half of ABX pattern, J=13.2, 2.8 Hz, 1H), 2.03-2.15 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-])=O.[C:14](N1C=CN=C1)([N:16]1C=CN=C1)=O.C(=O)=O>C1COCC1>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:16][CH3:14])=[O:13])=[CH:6][CH:5]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Agent: O=C=O
Solvent: C1CCOC1
Product: CNC(=O)Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
4-Nitrobenzeneacetic acid (16.6 g, 0.0916 mol) was dissolved in THF (200 mL) and carbonyldiimidazole (CDI, 15.6 g, 0.0963 mol) was added. Carbon dioxide evolution rapidly ensued and the reaction mixture was stirred at RT for 30 min. Gaseous methylamine was then bubbled through the mixture until it was distinctly basic to litmus paper. The THF was removed in vacuo and water (70 mL) was added. The solid material was collected by filtration and placed in a Parr bottle were palladium on carbon (10%, 3 g). A solution of EtOH (200 mL) and 1N HCl (50 mL) was added and the mixture was hydrogenated at 60 psi for 4 h. The reaction was filtered, concentrated in vacuo and the residue made basic with saturated aqueous Na2CO3. The aqueous mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give the product (6) (10.0 g, 66.6%) which was pure by NMR analysis.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5](O)=[CH:4][CH:3]=1.[C:11](=O)([O-])[O-:12].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Br:1][C:2]1[C:3]([O:12][CH3:11])=[CH:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(Br)ccc1O
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1ccc(C=O)cc1Br

Procedure:
5-Bromosalicylaldehyde (25 g, 124 mmol) was dissolved in acetone (300 ml) and anhydrous potassium carbonate (17.2 g, 124 mmol) was added. The mixture was heated and dimethyl sulfate (15.7 g, 124 mmol) was dropwise added over 45 min with gentle reflux. After the dropwise addition, the mixture was refluxed for 1 hr and cooled. Acetone was evaporated under reduced pressure. Toluene and water were added to the residue and the toluene layer was separated. The aqueous layer was extracted with toluene. The combined organic layer was washed with water and dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure to give the objective compound (27.3 g, quantitative) as colorless crystals.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=O.[C:8]([O:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])(=[O:11])[CH:9]=[CH2:10].C1N2CCN(CC2)C1.[O:28]1CCOCC1>>[OH:4][CH:1]([CH3:2])[O:5][C:6]([CH2:7][C:9](=[CH2:10])[C:8]([O:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:11])=[O:28]
Reactant: CCOC(=O)C=O
Reactant: C1COCCO1
Reactant: C=CC(=O)OCCN(CC)CC
Agent: C1CN2CCN1CC2
Product: C=C(CC(=O)OC(C)O)C(=O)OCCN(CC)CC
Yield: 54 %

Procedure:
51 g (0.5 mole) of ethyl glyoxylate, 85.5 g (0.5 mole) of N,N-diethylaminoethyl acrylate and 5 g (62.5 millimoles) of DABCO in 100 ml of absolute dioxane are reacted by a method similar to that described in Example 6. 74 g (54% of theory) of diethylaminoethyl 2-(1-hydroxycarbethoxymethyl)-acrylate are obtained.
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:42])[C@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.FC(F)(F)C(O)=O.[SH:50][C@@H:51]1[CH2:55][N:54](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[C@H:53]([CH:69]2[CH2:74][CH2:73][N:72]([CH3:75])[CH2:71][CH2:70]2)[CH2:52]1>C(#N)C.C(N(CC)C(C)C)(C)C>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])=[C:18]([S:50][C@@H:51]3[CH2:55][NH:54][C@H:53]([CH:69]4[CH2:74][CH2:73][N:72]([CH3:75])[CH2:71][CH2:70]4)[CH2:52]3)[C@H:19]([CH3:42])[C@H:20]12)[CH3:39]
Reactant: CN1CCC([C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@@H]3CN[C@H](C4CCN(C)CC4)C3)[C@H](C)[C@H]12
Temperature: 0 °C
Reaction time: 15 h
Yield: 69.7 %

Procedure:
To a solution of p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (2.50 g, 4.2 mmol) in acetonitrile (60ml), N,N-diisopropylethylamine was dropwise added in a nitrogen stream under cooling with ice, followed by dropwise adding a solution of (2S,4S)-4-mercapto-2-(N-methylpiperidin-4-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidine trifluoroacetic acid salt (2.30 g, 4.6 mmol, compound of Reference Example 37 in acetonitrile (60 ml). After the mixture was stirred at 0° C. for 15 hours, the precipitate was collected by filtration, washed with acetonitrile and dried to obtain p-nitrobenzyl (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2 -[(2S,4S)-2-(N-methylpiperidin-4-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (2.12 g, yield: 69.7%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([F:10])[CH:4]=1.CC([O-])(C)C.[K+].[O:17]1[CH2:22][CH2:21][CH2:20][O:19][CH:18]1[C:23]1[N:28]=[CH:27][C:26]([C:29]2[S:37][C:36]3[C:31](=[N:32][CH:33]=[CH:34][C:35]=3Cl)[CH:30]=2)=[CH:25][CH:24]=1.O>CS(C)=O>[O:17]1[CH2:22][CH2:21][CH2:20][O:19][CH:18]1[C:23]1[N:28]=[CH:27][C:26]([C:29]2[S:37][C:36]3[C:31](=[N:32][CH:33]=[CH:34][C:35]=3[O:9][C:6]3[CH:7]=[CH:8][C:3]([NH2:2])=[CH:4][C:5]=3[F:10])[CH:30]=2)=[CH:25][CH:24]=1
Reactant: Nc1ccc(O)c(F)c1
Reactant: Clc1ccnc2cc(-c3ccc(C4OCCCO4)nc3)sc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)nc4)sc23)c(F)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a stirred solution of 4-amino-2-fluorophenol hydrochloride (5.79 g, 35.4 mmol) in DMSO (40 mL) was added t-BuOK (8.66 g, 77.0 mmol). After 30 min, chloride 279 (10.70 g, 32.2 mmol) was added and the reaction mixture was heated at 100° C. for 1.5 h. More solution of 4-amino-2-fluorophenol HCl (860 mg, 7.70 mmol) and t-BuOK (0.86 g, 7.70 mmol) in DMSO (4 mL) was added to the reaction mixture that was heated at 100° C. for an additional 15 min. The reaction mixture was then poured into water (300 mL) to form a precipitate that was collected by filtration, dried under vacuum and triturated with MTBE to afford the title compound 280 (12.39 g, 29.3 mmol, 91% yield) as a beige solid. MS (m/z): 424.39 (M+H).
Reaction SMILES: [CH3:1][CH:2]([CH3:28])[CH2:3][C@H:4]([C:20]1([C:25]([NH2:27])=[O:26])[CH2:24][CH:23]=[CH:22][CH2:21]1)[C:5](=[O:19])[NH:6][CH:7]1[C:13](=[O:14])[NH:12][C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[CH2:9][CH2:8]1.C([O-])([O-])=O.[K+].[K+].[F:35][C:36]1[CH:50]=[CH:49][CH:48]=[CH:47][C:37]=1[O:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH2:42]Br>CC#N>[F:35][C:36]1[CH:50]=[CH:49][CH:48]=[CH:47][C:37]=1[O:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH2:42][N:12]1[C:13](=[O:14])[CH:7]([NH:6][C:5]([CH:4]([C:20]2([C:25]([NH2:27])=[O:26])[CH2:21][CH:22]=[CH:23][CH2:24]2)[CH2:3][CH:2]([CH3:28])[CH3:1])=[O:19])[CH2:8][CH2:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]1=2
Reactant: Fc1ccccc1Oc1cccc(CBr)c1
Reactant: CC(C)C[C@@H](C(=O)NC1CCc2ccccc2NC1=O)C1(C(N)=O)CC=CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)CC(C(=O)NC1CCc2ccccc2N(Cc2cccc(Oc3ccccc3F)c2)C1=O)C1(C(N)=O)CC=CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.6 %

Procedure:
To a solution of 20 (11 mg) in CH3CN (2 mL) was added K2CO3 (8 mg) and 3-(2-fluorophenoxy)benzyl bromide 22 (12 mg). The reaction mixture was stirred at rt for 20 hrs before the solvent was removed under pressure. The crude product was purified by flash chromatography to give compound 23 (77%, 13 mg). 1H NMR (300 MHz, CDCl3) 7.32-6.80 (m, 12H), 5.72 (m, 1H), 5.58 (m, 1H), 5.34 (d, 1H), 4.72 (d, 1H), 4.48 (m, 1H), 3.18 (m, 1H), 2.70-2.20 (m, 8H), 1.95-1.78 (m, 2H), 1.42 (m, 1H), 1.12 (m, 1H), 0.92-0.80 (q, 6H); MS [M+H]+ 584.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:23]3[O:22][C:21]([C:24]([O-])=[O:25])=[CH:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.[Li+].Cl.[CH3:29][S:30]([C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1)(=[O:32])=[O:31]>>[CH3:29][S:30]([C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH:38][C:24]([C:21]2[O:22][C:23]3[C:15]([N:12]4[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)[CH2:10][CH2:11]4)=[CH:16][CH:17]=[CH:18][C:19]=3[CH:20]=2)=[O:25])=[CH:35][CH:34]=1)(=[O:31])=[O:32]
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Reactant: O=C([O-])c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1
Agent: Cl
Agent: [Li+]
Product: CS(=O)(=O)c1ccc(CNC(=O)c2cc3cccc(N4CCN(CCc5ccccn5)CC4)c3o2)cc1

Procedure:
The compound was prepared according to the procedure disclosed in Example 1 starting from lithium 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (60 mg, 0.16 mmol) and 4-methylsulphonylbenzylamine hydrochloride (42 mg, 0.19 mmol). Yield: 38 mg (43%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.N[CH:23]1[CH2:26][CH2:25][CH:24]1[OH:27].C[N:29](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([NH:29][CH:26]3[CH2:25][CH:24]([OH:27])[CH2:23]3)=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1ncnc2ccc(-c3cc(F)cc(C(=O)O)c3)nc12
Reactant: NC1CCC1O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ncnc2ccc(-c3cc(F)cc(C(=O)NC4CC(O)C4)c3)nc12

Procedure:
Following the same reaction and purification procedure, the acid 3 (50 mg, 0.17 mmol) was reacted with 2-aminocyclobutanol (CAS 4640-44-2) (30 mg, 0.35 mmol), HATU (135 mg, 0.35 mmol) and DIPEA (0.15 mL, 0.9 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-5-fluoro-N-(3-hydroxycyclobutyl)benzamide 8 as a mixture of cis and trans isomer. LC/MS (ESI+): m/z 354 (M+H). 1H NMR (400 MHz, DMSO) δ 8.81 (d, J=6.9 Hz, 1H), 8.63 (d, J=10.2 Hz, 1H), 8.54 (dd, J=10.1, 8.9 Hz, 3H), 8.44 (s, 1H), 8.31 (s, 1H), 8.20 (d, J=8.8 Hz, 1H), 8.03 (s, 1H), 7.73 (d, J=8.2 Hz, 2H), 5.15 (d, J=5.4 Hz, 1H), 5.05 (d, J=5.2 Hz, 1H), 4.48 (d, J=6.2 Hz, 1H), 4.37 (d, J=4.7 Hz, 1H), 4.04-3.84 (m, 2H), 2.96-2.84 (m, 1H), 2.69-2.54 (m, 2H), 2.39-2.28 (m, 1H), 2.21 (ddd, J=12.6, 8.1, 4.7 Hz, 1H), 1.97 (ddd, J=17.2, 8.7, 2.7 Hz, 2H).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:22]=[C:21]([CH2:23]O)[CH:20]=[CH:19][C:5]=1[O:6][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[C:8]([O:10][CH3:11])=[O:9])[CH3:3].P(Br)(Br)[Br:26]>C(Cl)(Cl)(Cl)Cl>[CH3:1][CH:2]([C:4]1[CH:22]=[C:21]([CH2:23][Br:26])[CH:20]=[CH:19][C:5]=1[O:6][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[C:8]([O:10][CH3:11])=[O:9])[CH3:3]
Reactant: COC(=O)C(Oc1ccc(CO)cc1C(C)C)c1cccc(Cl)c1
Reactant: BrP(Br)Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Oc1ccc(CBr)cc1C(C)C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.5 %

Procedure:
To a solution of 0.110 g (0.31 mmol) of the product of Step A dissolved in 1.0 mL of carbon tetrachloride was added 0.03 mL (1.6 mmol) of phosphorous tribromide and the reaction mixture was stirred at room temperature for 10 minutes. Carbon tetrachloride was evaporated from the reaction mixture several times to remove the hydrogen bromide, then the residue was purified on a silica gel flash chromatography column eluted with 15% EtOAc-hexane. The purified fractions were evaporated in vacuo affording 0.104 g (80%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=[C:3]1[C:10](Cl)=[O:11].C[CH:14]([NH:16]P(OC1C=CC(Cl)=CC=1Cl)(OC)=S)C.C[CH2:31][N:32]([CH2:35][CH3:36])[CH2:33]C>C(Cl)Cl>[CH3:31][N:32]([CH3:33])[CH2:35][CH2:36][CH2:14][NH:16][C:10]([C:3]1[N:2]([CH3:1])[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=1)=[O:11]
Reactant: COP(=S)(NC(C)C)Oc1ccc(Cl)cc1Cl
Reactant: Cn1cc([N+](=O)[O-])cc1C(=O)Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CCCNC(=O)c1cc([N+](=O)[O-])cn1C
Reaction time: 8 h
Yield: 74 %

Procedure:
A solution of 1-methyl-4-nitro-1H-pyrrole-2-carbonyl chloride (0.254 g, 1.35 mmol; see Preparation 1(ii) above) in DCM (10 mL), is added dropwise to a solution of DMPA (0.153 g, 5.05 mmol) (Aldrich), NEt3 (0.152 g, 1.5 mmol), in DCM (10 mL) over 15 min. The resulting solution was allowed to stir overnight, before quenching the reaction with a 5% NaOH solution (20 mL). The DCM fraction was then dried over MgSO4, filtered and the solvent removed under reduced pressure to yield the sub-title compound (0.254 g, 74%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][C:6]=1[F:15])(=[O:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>C(O)(=O)C>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([N+:16]([O-:18])=[O:17])[C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][C:6]=1[F:15])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(NC(C)=O)c(F)c1
Solvent: CC(=O)O
Product: CC(=O)Nc1cc([N+](=O)[O-])c(NC(C)=O)cc1F
Temperature: 40 °C
Reaction time: 2 h

Procedure:
157.5 g (0.75 mol) of the 1,4-bisacetylamino-2-fluorobenzene obtained above under B. are initially introduced into 630 g of glacial acetic acid, and a mixture of 42 g of glacial acetic acid and 51 g of nitric acid (density 1.5) is added dropwise in the course of 2 hours. The mixture is subsequently stirred at 40° C. for a further 2 hours and cooled to 15° C. After the product which has precipitated has been filtered off, it is washed twice with 50 ml of glacial acetic acid each time and dried at 50° C. in a vacuum cabinet.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH:7]([N:9]1[C:15](=[O:16])[CH:14]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:27])[CH2:13][CH2:12][C:11](=[O:28])[NH:10]1)[CH3:8])(C)(C)[CH3:2].[C:30]([O-])([O-])=O.[K+].[K+].IC>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1COCC1.ClCCl>[CH2:1]([O:5][C:6](=[O:29])[CH:7]([N:9]1[C:15](=[O:16])[CH:14]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:27])[CH2:13][CH2:12][C:11](=[O:28])[N:10]1[CH3:30])[CH3:8])[CH3:2]
Reactant: CC(C(=O)OC(C)(C)C)N1NC(=O)CCC(N2C(=O)c3ccccc3C2=O)C1=O
Reactant: O=C([O-])[O-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Solvent: ClCCl
Product: CCOC(=O)C(C)N1C(=O)C(N2C(=O)c3ccccc3C2=O)CCC(=O)N1C
Temperature: 25 °C
Reaction time: 120 h
Yield: 91 %

Procedure:
A mixture of 2-[6-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3,7-dioxo-[1,2]diazepan-1-yl]-propionic acid tert-butyl ester (14) (314 mg, 0.84 mmol), benzyltriethylammonium chloride (30 mg, 0.13 mmol), K2CO3 (406 mg, 2.94 mmol) and iodomethane (360 mg, 2.53 mmol) in THF (8 mL) was stirred at room temperature for five days. The mixture was diluted with dichloromethane (70 mL), washed with water three times, dried over anhydrous Na2SO4, filtered and evaporated in vacuo to dryness to afford 296 mg (91% yield) of the title compound as a mixture of diastereomers. 1H-NMR (500 MHZ, CDCl3) δ 1.25-1.35 (m, 2.5H), 1.47-1.52 (m, 0.5H), 1.60-1.75 (m, 3H), 2.37-2.52 (m, 2H), 3.05-3.14 (m, 0.5H), 3.30-3.45 (m, 3.5H), 3.45-3.58 (m, 1H), 4.14-4.28 (m, 2H), 4.52-4.58 (m, 0.5H), 4.80-4.87 (m, 0.5H), 5.13-5.28 (m, 1H), 7.70-7.90 (m, 4H). Analytical HPLC: 6.00 and 6.11 min. LC-MS (ES+): m/e=388 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:16]=3[CH:15]3[CH:10]([CH2:11][CH2:12][N:13]([CH3:26])[CH2:14]3)[N:9]=2)=[CH:4][CH:3]=1.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O.[OH-].[Na+]>N1C=CC=CC=1>[C:27]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:16]=3[C@H:15]3[C@H:10]([CH2:11][CH2:12][N:13]([CH3:26])[CH2:14]3)[N:9]=2)=[CH:4][CH:3]=1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1cc2c(cc1OC)C1CN(C)CCC1N=C2c1ccc(N)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: COc1cc2c(cc1OC)[C@@H]1CN(C)CC[C@@H]1N=C2c1ccc(NC(=O)c2ccccc2)cc1
Reaction time: 15 h

Procedure:
2 g of 6-(4-aminophenyl)-8,9-dimethoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridine are dissolved in 30 ml of pyridine, 1 g of benzoylchloride is added to the solution and the reaction mixture is allowed to stand at room temperature for 15 hours. The reaction mixture is then treated with 10 ml of water, allowed to stand for 10 minutes and is then reduced in volume under vacuum. The resulting residue is rendered alkaline with dilute sodium hydroxide and is then extracted with methylenechloride. After evapaorating off of the organic phase, the crude product is dissolved in ethanol and rendered acid with an ethanolic hydrochloric acid solution, whereby the dihydrochloride of the title compound crystallizes out in yellowish prisms of M.P. 240°-245°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.[C:11](#[N:15])[CH2:12][C:13]#[N:14].O>C(O)C.N1CCCCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[C:12]([C:11]#[N:15])[C:13]#[N:14]
Reactant: N#CCC#N
Reactant: O=Cc1ccc(O)c(O)c1
Solvent: CCO
Solvent: C1CCNCC1
Solvent: O
Product: N#CC(C#N)=Cc1ccc(O)c(O)c1
Temperature: 70 °C
Yield: 85.3 %

Procedure:
To 11 g (80 mmol) of 3,4-dihydroxybenzaldehyde and 5.5 g (83 mmol) of malononitrile in 40 ml of ethanol, 7 drops of piperidine were added and the mixture was heated at 70° C. for 0.5-1 hour and then poured into water. The resulting solid precipitate was separated by filtration to give 12.7 g (86% yield) of a yellow solid, m.p. 225° C.
Reaction SMILES: [N:1]1[N:2]2[CH:10]=[CH:9][CH:8]=[C:3]2[C:4]([NH2:7])=[N:5][CH:6]=1.C=O.Cl.[O:14]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[C:21]([O-])(=O)C.[K+]>C(O)(=O)C.O>[O:14]1[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][C:10]2[N:2]3[C:3]([C:4]([NH2:7])=[N:5][CH:6]=[N:1]3)=[CH:8][CH:9]=2)[CH2:16][CH2:15]1
Reactant: C1CNCCOC1
Reactant: Nc1ncnn2cccc12
Reactant: CC(=O)[O-]
Agent: C=O
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ncnn2c(CN3CCCOCC3)ccc12
Temperature: 60 °C
Yield: 92 %

Procedure:
Pyrrolo[2,1-f][1,2,4]triazin-4-amine (4000 mg, 29.8 mmol) was dissolved in acetic acid (160 mL). 37% wt formaldehyde in water is added (2.90 mL, 35.8 mmol) followed by 1,4-oxazepane hydrochloride (4.92 g, 35.8 mmol) and potassium acetate (5.27 g, 53.7 mmol). The reaction was heated at 60° C. under a nitrogen atmosphere overnight then cooled to room temperature. The reaction was concentrated under vacuum. The residue was partitioned between EtOAc (300 mL) and saturated aqueous bicarbonate (150 mL). The aqueous layer is extracted with EtOAc (5×100 mL). The combined organics were washed with brine (100 mL) then dried with Na2SO4 to yield 6.78 g (92%) of desired product.
Reaction SMILES: [S:1]1[CH:5]=[C:4](B(O)O)[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[CH3:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.O=[CH:23][C:24]([OH:26])=[O:25]>C(#N)C>[S:1]1[CH:5]=[C:4]([CH:23]([N:14]([CH3:13])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:24]([OH:26])=[O:25])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: O=CC(=O)O
Reactant: OB(O)c1csc2ccccc12
Reactant: CNc1ccccc1
Solvent: CC#N
Solvent: O
Product: CN(c1ccccc1)C(C(=O)O)c1csc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.5 %

Procedure:
A mixture of benzo[b]thiophen-3-ylboronic acid (300 mg, 1.68 mmol), N-methylaniline (184 μl, 1.68 mmol) and 2-oxoacetic acid hydrate (155 mg, 1.65 mmol) in acetonitrile (20 ml) was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the crude product was purified by flash chromatography (DCM/MeOH=95/5) to obtain 2-(benzo[b]thiophen-3-yl)-2-(methyl(phenyl)amino)acetic acid (351 mg, 70% yield).