Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([CH3:20])([CH3:19])[CH2:3][N:4]1[C:16]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH2:17][OH:18].C(N(CC)CC)C.[C:28](OC(=O)C)(=[O:30])[CH3:29].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:28]([O:18][CH2:17][C:5]1[N:4]([CH2:3][C:2]([F:1])([CH3:20])[CH3:19])[C:16]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=1)(=[O:30])[CH3:29]
Reactant: CC(C)(F)Cn1c(CO)nc2cnc3cccnc3c21
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCc1nc2cnc3cccnc3c2n1CC(C)(C)F
Reaction time: 2 h
Yield: 90.1 %

Procedure:
A solution of [1-(2-fluoro-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]methanol (1.53 g, 5.58 mmol) dissolved in 50 mL of CH2Cl2 was treated with triethylamine (1.55 mL, 11.2 mmol), acetic anhydride (663 μL; 6.70 mmol), and 10 mg of 4-(dimethylamino)pyridine (DMAP). After stirring for 2 hours, the reaction mixture was treated with saturated NaHCO3 solution and the layers were separated. The organic portion was washed successively with 3.5% NaH2PO4 solution, H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 40-60% acetone/hexanes) gave 1.59 g of [1-(2-fluoro-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]methyl acetate as an off-white powder.
Reaction SMILES: [F:1][C:2]1([F:20])[CH2:7][CH2:6][CH:5]([CH2:8]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:4][CH2:3]1.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C)C=O.ClCCl>[N:21]([CH2:8][CH:5]1[CH2:6][CH2:7][C:2]([F:20])([F:1])[CH2:3][CH2:4]1)=[N+:22]=[N-:23]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC(F)(F)CC2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: [N-]=[N+]=NCC1CCC(F)(F)CC1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
To a solution of toluene-4-sulfonic acid 4,4-difluorocyclohexylmethyl ester (100 mg, 0.33 mmol)) in N,N-Dimethylformamide (0.5 mL) was added sodium azide (32 mg, 0.49 mmol). The reaction mixture was stirred at 90° C. for 90 min, cooled to room temperature and diluted with dichloromethane (5 mL). The organic layer was washed with water (2×5 mL), collected, dried over anhydrous sodium sulfate, filtered, and concentrated to provide the title compound which was used without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:39](=[O:40])[N:12]2[C:13]([C:23]([O:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[C:14]([N:17]3[CH2:22][CH2:21]O[CH2:19][CH2:18]3)[CH2:15][S:16][C@H:11]12)=[O:8].N1CCOC[CH2:42]1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:39](=[O:40])[N:12]2[C:13]([C:23]([O:25][CH:26]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:24])=[C:14]([N:17]3[CH2:18][CH2:19][CH2:42][CH2:21][CH2:22]3)[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(N3CCOCC3)CS[C@H]12
Reactant: C1COCCN1
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(N3CCCCC3)CS[C@H]12

Procedure:
By employing the procedures and starting material of Example 2 and substituting piperidine for morpholine the title compound was prepared.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][C@H:12]1[C:16](=[O:17])[O:15][C:14](=[O:18])[NH:13]1>C(OCC)(=O)C.CN(C)C1C=CN=CC=1>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:13]2[C@@H:12]([CH3:11])[C:16](=[O:17])[O:15][C:14]2=[O:18])=[O:7])=[CH:4][CH:3]=1
Reactant: C[C@@H]1NC(=O)OC1=O
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)N2C(=O)OC(=O)[C@@H]2C)cc1
Reaction time: 2 h
Yield: 32.6 %

Procedure:
p-Methylbenzoyl chloride (309 mg, 2.0 mmol) was dissolved in ethyl acetate (5 mL), followed by the addition of (S)-4-methyl-2,5-oxazolidinedione (L-alanine-NCA) (230 mg, 2.0 mmol) under ice cooling. Further, a solution of 4-dimethylaminopyridine (244 mg, 2.0 mmol) in ethyl acetate (10 mL) was added dropwise under ice cooling over 20 minutes. After the resulting mixture was stirred as was at 0° C. for 2 hours, a precipitated salt was filtered off, and the filtrate was concentrated under reduced pressure. The concentration residue was re-dissolved in a mixed solvent consisting of ethyl acetate (5 mL) and hexane (5 mL), and insoluble matter was filtered off. The filtrate was concentrated under reduced pressure to afford the title compound (152 mg, 33%) as a colorless clear syrup.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]([NH2:14])[NH:12][CH:13]=1.CC([O-])=O.[Na+].[Cl:20][C:21]1[CH:34]=[CH:33][C:24]([CH:25]=[C:26]([C:30](=O)[CH3:31])[C:27]([NH2:29])=[O:28])=[CH:23][C:22]=1[F:35]>C1COCC1.CO>[Cl:20][C:21]1[CH:34]=[CH:33][C:24]([CH:25]2[N:12]3[CH:13]=[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[N:10]=[C:11]3[NH:14][C:30]([CH3:31])=[C:26]2[C:27]([NH2:29])=[O:28])=[CH:23][C:22]=1[F:35]
Reactant: COc1ccccc1-c1c[nH]c(N)n1
Reactant: CC(=O)C(=Cc1ccc(Cl)c(F)c1)C(N)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccccc1-c1cn2c(n1)NC(C)=C(C(N)=O)C2c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 54.4 %

Procedure:
A mixture of 4-(2-methoxyphenyl)-1H-imidazol-2-amine (0.85 g, 4.5 mmol) and NaOAc (267.3 mg, 4.95 mmol) in THF (5 mL) and MeOH (1.5 mL) was stirred at room temperature for 20 min and followed by addition of 2-(4-chloro-3-fluorobenzylidene)-3-oxobutanamide (1.09 g, 4.5 mmol). The reaction mixture was then heated to 70° C. for 2 h and evaporated under reduced pressure. The residue was suspended in THF, and the slurry mixture was filtered to give 5-(4-chloro-3-fluorophenyl)-2-(2-methoxyphenyl)-7-methyl-5,8-dihydroimidazo[1,2-a]pyrimidine-6-carboxamide (1.01 g, 54.4%) as a yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:57])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[CH:16][C:15]([C:28](=[O:44])[NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:14][C:13]=2[C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=2)=[CH:6][C:5]=1[O:55][CH3:56].[OH-].[Na+]>C1COCC1.CCO>[CH3:56][O:55][C:5]1[CH:6]=[C:7]([CH2:10][O:11][C:12]2[C:13]([C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:52])([F:53])[F:54])[CH:46]=3)=[CH:14][C:15]([C:28](=[O:44])[NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[CH:16][C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:27])[F:26])[CH:19]=2)[CH:8]=[CH:9][C:4]=1[C:3]([OH:57])=[O:2]
Reactant: COC(=O)c1ccc(COc2c(-c3cccc(C(F)(F)F)c3)cc(C(=O)NCCCCCCCCc3ccccc3)cc2-c2cccc(C(F)(F)F)c2)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(COc2c(-c3cccc(C(F)(F)F)c3)cc(C(=O)NCCCCCCCCc3ccccc3)cc2-c2cccc(C(F)(F)F)c2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of 2-methoxy-4-[5′-(8-phenyl-octylcarbamoyl)-3,3″-bis-trifluoromethyl-[1,1′;3′,1″]terphenyl-2′yloxymethyl]-benzoic acid methyl ester (0.352 g, 0.44 mmol, 1 eq) in THF/EtOH (3/2) (10 mL) was added 1M NaOH (4 mL) and the reaction was stirred at rt overnight. It was then concentrated in vacuo, diluted with H2O, and acidified with 2M HCl to pH 1. It was extracted with EtOAc, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (20% EtOAc/hexane+1% Formic acid) to afford the title compound (0.342 g, 865) as a white foam. 1H NMR (DMSO-d6) δ 12.50 (bs, 1H); 8.59 (t, 1H); 7.99-7.92 (m, 6H); 7.80-7.68 (m, 4H); 7.37 (d, 1H); 7.26-7.10 (m, 5H); 6.38 (s, 1H); 6.30 (d, 1H); 4.21 (s, 2H); 3.58 (s, 3H); 3.26 (dd, 2H); 2.52 (t, 2H); 1.53 (m, 4H); 1.28 (m, 8H); IR (KBr) 3350, 2950, 2850, 1720, 1640, 1620, 1550, 1495, 1475, 1415, 1320, 1160, 1150, 1120, 1095, 1080, 1030 cm−1; mass spectrum [(+)APCI], m/z 778 (M+H)+; Anal. Calcd. for C44H41F6NO5: C, 67.95; H, 5.31; N, 1.80, Found: C, 67.22; H, 5.22; N, 1.74.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]([CH3:14])[CH3:13].[CH3:15][N:16]1[CH:20]=[C:19]([NH2:21])[CH:18]=[N:17]1.CCN(C(C)C)C(C)C>C(O)CCC>[F:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][N:6]2[CH:12]([CH3:14])[CH3:13])=[C:2]([NH:21][C:19]2[CH:18]=[N:17][N:16]([CH3:15])[CH:20]=2)[N:10]=1
Reactant: CC(C)n1cnc2c(Cl)nc(F)nc21
Reactant: Cn1cc(N)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)n1cnc2c(Nc3cnn(C)c3)nc(F)nc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 6-chloro-2-fluoro-9-isopropyl-9H-purine (200 mg, 0.932 mmol), as prepared in step 1 of the alternate method of Example 2, in nBuOH, (4.66 mL) was added 1-methyl-1H-pyrazol-4-amine (109 mg, 1.12 mmol) and DIPEA (482 mg, 3.73 mmol) and the mixture stirred at ambient temperature for 6 hr to yield crude 2-fluoro-9-isopropyl-N-(1-methyl-1H-pyrazol-4-yl)-9H-purin-6-amine. (S)-3-(methylsulfonyl)-N-(pyrrolidin-3-yl)propanamide hydrochloride (289 mg, 1.12 mmol) was then added to the reaction mixture and heated at 100° C. for 16 hr. LCMS showed unreacted intermediate so the reaction was heated at 110° C. for another 24 hr. The reaction was then cooled to ambient temperature and potassium tert-butoxide (3.73 mL, 3.73 mmol) was added and the resulting mixture stirred at ambient temperature for 30 min. Water was added and the reaction was extracted with DCM (3×50 mL), then the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were dried with Na2SO4, concentrated, loaded onto silica and purified via flash chromatography using 0-20% EtOH/EtOAc to give the title compound (290 mg, 78% yield) as a pink solid, 1H NMR (400 MHz, DMSO-d6) δ ppm 9.56 (s, 1 H) 8.38 (d, J=6.72 Hz, 1 H) 7.97 (s, 1 H) 7.89 (s, 1 H) 7.75 (s, 1 H) 6.20-6.34 (m, 1 H) 6.05-6.18 (m, 1 H) 5.60 (dd, J=10.03, 2.32 Hz, 1 H) 4.56-4.73 (m, 1 H) 4.43 (br. s., 1 H) 3.76-3.92 (m, 4 H) 3.68 (d, J=5.14 Hz, 2 H) 3.43-3.51 (m, 1 H) 2.15-2.28 (m, 1 H) 1.87-1.99 (m, 1 H) 1.51 (d, J=6.85 Hz, 6 H). m/z for C19H25N9O 397.25 and 396.30 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH:2]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:15][CH:14]=2)[CH:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C(O)c1ccc(-c2cccnc2)cc1
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)c1ccc(-c2cccnc2)cc1

Procedure:
In a similar manner to Referential Example 12 except for the use of 4-(3-pyridyl)benzoic acid and 1-tert-butoxycarbonyl-3-ethoxycarbonylpiperazine as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[NH2:16][C@@H:17]([C:21]([OH:23])=[O:22])[C@@H:18]([CH3:20])[OH:19]>>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C:13]([NH:16][C@@H:17]([C:21]([OH:23])=[O:22])[C@@H:18]([CH3:20])[OH:19])=[O:15])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[C@@H](O)[C@@H](N)C(=O)O
Reactant: CCCCOc1ccc(CC(=O)O)cc1
Product: CCCCOc1ccc(CC(=O)N[C@@H](C(=O)O)[C@@H](C)O)cc1

Procedure:
4-Butoxyphenylacetic acid (288 mg, 1.38 mmol) is converted to the acid chloride and added to D-allo-Thr (150 mg, 1.26 mmol) to get 2c-9, following the procedure described in Example 6. The crude product is purified by chromatography (2.5×18 cm column, gradient 4% CH3OH and 0.3% HOAc in CH2Cl2): NMR δ 0.96 (t, J=7.4, 3 H), 1.14 (d, J=5.8, 3 H), 1.47 (m, 2 H), 1.74 (m, 2 H), 3.53 (br s, 2 H), 3.91 (t, J≃6.5, 2 H), 4.10 (br s, 1 H), 4.53 (br s, 1 H), 4.90 (br s, >2 H), 6.76 (br d, J=6.0, 1 H), 6.84 (d, J=8.4, 2 H), 7.13 (d, J=8.4, 2 H); MS (HR-EI) m/z 309.1567 (M calcd. for C16H23NO5, 309.1576) [α]D26 -26±2 (CHCl3); m.p. 90°-94° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH2:12][CH2:13][OH:14].[CH2:15]([Sn](CCCC)(CCCC)C=C)[CH2:16]CC.[Li+].[Cl-].CCOC(C)=O>C1(C)C=CC=CC=1.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>[CH:15]([C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH2:12][CH2:13][OH:14])=[CH2:16]
Reactant: O=C1OCc2c1ccc(Br)c2CCO
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=Cc1ccc2c(c1CCO)COC2=O
Temperature: 105 °C

Procedure:
A mixture of 5-bromo-4-(2-hydroxyethyl)-2-benzofuran-1(3H)-one (0.460 g, 1.78 mmol), tributyl(vinyl)tin (0.676 g, 2.13 mmol), LiCl (0.224 g, 5.33 mmol) and Pd (PPh3)4 (0.10 g, 0.087 mmol) in toluene (50 mL) was heated at 100-110° C. under N2 overnight after which TLC indicated that the reaction had gone to completion. Next, EtOAc (100 mL) was poured into the solution and it was washed with brine, then water, then dried over Na2SO4, filtered and concentrated to dryness. The residue was then absorbed onto silica gel and separated over silica column to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[C:11]([NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].N1C=CC=CC=1>C(Cl)Cl>[C:14]([O:13][C:11](=[O:12])[NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:23][CH:22]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.6 %

Procedure:
4-chlorobenzeneboronic acid (2.05 eq, 2.05 g), N-boc tyramine (1 eq, 6.55 mmol, 1.60 g), cooper(II)-acetate (1.01 eq, 1.20 g) and pyridine (5 eq, 2.64 ml) were dissolved in 70 ml of dry DCM. In the solution were added 4 Å molecular sieves (3 g) and the resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was then filtered over a celite pad, it was diluted with 150 ml of diethyl ether and was subsequently washed with 150 ml of 0.5 N HCl water solution, 150 ml of water and 150 ml of brine. The organic phase was dried, the solvent was evaporated and the resulting crude was purified by chromatography on BIOTAGE SP1 purification device using 50 g normal phase silica SNAP column and cyclohexane/EtOAc solvent system (gradient 5-30% of EtOAc in 20 column volumes). Solvent from the gathered fractions of appropriate composition was evaporated and obtained was {2-[4-(4-chloro-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (1.7 g, yield=68.14%, purity=94%). MS: [M−H]−=346.13 1H NMR (300 MHz; CDCl3) δ/ppm 1.42 (s, 9H), 2.75 (t, J=7.0 Hz, 2H), 3.35 (m, 2H), 6.87-6.95 (m, 4H), 7.14 (d, J=8.45 Hz, 2H), 7.22-7.28 (m, 2H)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH2:26]([N:28]1[CH2:32][CH2:31][C@H:30]([CH2:33][NH2:34])[CH2:29]1)[CH3:27].C(N(CC)CC)C>CS(C)=O>[CH2:26]([N:28]1[CH2:32][CH2:31][C@H:30]([CH2:33][NH:34][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([NH:11][C:12]2[C:21]([C:22]([OH:24])=[O:23])=[C:20]3[C:15]([CH:16]4[CH2:25][CH:17]4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH2:29]1)[CH3:27]
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Reactant: CCN1CC[C@H](CN)C1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCN1CC[C@H](CNc2ccccc2S(=O)(=O)Nc2ccc3c(c2C(=O)O)OCC2CC32)C1
Temperature: 140 °C
Yield: 22 %

Procedure:
A solution of (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (Intermediate 67, 0.105 g), ((R)-1-ethylpyrrolidin-3-yl)methyl-amine (Intermediate 163, 0.5 g) and triethylamine (0.5 g) in DMSO (1 mL) was stirred and heated at 140° C. overnight. After cooling, the mixture was concentrated under vacuum and the residue was purified by chromatogrpahy on silica, eluting with a mixture of methanol and DCM (5%). The product was purified by HPLC (C18) to give (1aRS,7bSR)-5-{2-[((R)-1-ethylpyrrolidin-3-ylmethyl)amino]benzene-sulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]-chromene-4-carboxylic acid (0.03 g) as a white solid,
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([CH:18]=[O:19])[CH:12]=2)[CH:3]=1.[H-].[Na+].[CH3:22]I>CN(C=O)C.O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[C:15]([O:17][CH3:22])[CH:14]=[C:13]([CH:18]=[O:19])[CH:12]=2)[CH:3]=1
Reactant: CI
Reactant: N#Cc1ccc(Cl)cc1Oc1cc(O)cc(C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(Oc2cc(Cl)ccc2C#N)c1
Reaction time: 16 h

Procedure:
4-Chloro-2-(3-formyl-5-hydroxyphenoxy)benzonitrile (0.20 g, 0.75 mmol) in DMF (5 ml) was treated with sodium hydride (60% in mineral oil, 30 mg, 0.78 mmol) followed after 10 min by methyl iodide (0.1 ml). After 16 h, a further amount of sodium hydride (8 mg) and methyl iodide (0.1 ml) were added. After 3 h, the mixture was diluted with water, extracted with ethyl acetate, the extracts washed with water, dried over sodium sulphate and evaporated to give the sub-title compound as a pale yellow solid (213 mg).
Reaction SMILES: [C:1]([CH2:3][CH:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[O:5][P:6](Cl)Cl)#[N:2].C[Si]([C:17]1[NH:18][CH:19]=[C:20]([CH3:22])[N:21]=1)(C)C>C1(C)C=CC=CC=1>[C:1]([CH2:3][CH:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[O:5][P:6]([C:17]1[NH:18][CH:19]=[C:20]([CH3:22])[N:21]=1)[C:17]1[NH:18][CH:19]=[C:20]([CH3:22])[N:21]=1)#[N:2]
Reactant: CC(C)(C)C(CC#N)OP(Cl)Cl
Reactant: Cc1c[nH]c([Si](C)(C)C)n1
Solvent: Cc1ccccc1
Product: Cc1c[nH]c(P(OC(CC#N)C(C)(C)C)c2nc(C)c[nH]2)n1
Reaction time: 0.08 h

Procedure:
To toluene (5 ml) there were added 0.332 g (1.46 mmol) of 2-cyano-1-tert-butylethoxydichlorophosphine and 0.495 g (3.21 mmol) of trimethylsilyl-4-methylimidazole under an argon atmosphere at room temperature, and reaction was conducted for 5 minutes. After by-product chlorotrimethylsilane and toluene were removed under reduced pressure for 10 minutes at room temperature, the residual toluene and excess trimethylsilyl-4-methylimidazole were removed under reduced pressure for 2 hours at 40° C. to obtain 2-cyano-1-tert-butylethoxybis(4-methylimidazolyl)phosphine as a colorless transparent oil. Under an argon atmosphere at room temperature, this 2-cyano-1-tert-butylethoxybis(4-methylimidazolyl)phosphine was dissolved in 2.9 ml of chloroform-d, and the solution (0.5 M) was added to 0.794 g (1.46 mmol) of 5′-O-(4,4′-dimethoxytrityl)thymidine that had been dried under reduced pressure for 2 hours. Upon reaching homogeneity, the mixture was allowed to stand overnight for reaction to obtain a nucleotide derivative represented by the formula (2-22) below. The 31P NMR of the obtained compound (external standard: (CH3O)3P=140 ppm, CDCl3) δ was 127.9, 128.2, 128.4, 130.8 ppm (measuring the 31P NMR spectrum with a 161.7 MHz NMR measuring apparatus).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH:5]2[OH:12].[Cl:13][C:14]1[CH:15]=[C:16](O)[CH:17]=[CH:18][CH:19]=1>CO.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH:5]2[O:12][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:13])[CH:19]=1
Reactant: OC1CCNc2ncc(Br)cc21
Reactant: Oc1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: Clc1cccc(OC2CCNc3ncc(Br)cc32)c1
Yield: 60 %

Procedure:
6-Bromo-1,2,3,4-tetrahydro-[1,8]naphthyridin-4-ol (225 mg) was reacted with 3-chlorophenol (0.30 mL) as in General Procedure 12. Basic alumina chromatography using a gradient of 0-1% methanol/methylene chloride as the eluting solvent gave the title compound as a white film (60% yield). LCMS: m/z=339 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.00 (m, 1H), 2.21 (m, 1H), 3.40 (m, 1H), 3.51 (m, 1H), 5.04 (s, 1H), 5.27 (t, J=3.9 Hz, 1H), 6.87 (d, J=8.3 Hz, 1H), 7.00 (m, 2H), 7.24 (m, 1H), 7.48 (d, J=2.1 Hz, 1H), 8.06 (d, J=2.1 Hz, 1H).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:18]1([OH:23])[CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:23][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OC1CCCC1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Product: N=C(OC1CCCC1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and cyclopentanol there is obtained cyclopentyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, 1H-NMR(CDCl3): 1.5-2.1 (8H), 4.2 (s, 4H), 4.67 (broad s, NH), 5.1 (m, OCH), 7.3-7.7 (8H).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[CH3:4][S:5]([C:7](SC)=[CH:8][N+:9]([O-:11])=[O:10])=O>CO>[CH3:4][S:5][C:7]([NH:3][CH2:1][CH3:2])=[CH:8][N+:9]([O-:11])=[O:10]
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Reactant: CCN
Solvent: CO
Product: CCNC(=C[N+](=O)[O-])SC
Yield: 28.4 %

Procedure:
A solution in methanol (5 ml) of ethylamine (225 mg) was added dropwise over 2 minutes to a stirred solution in methanol (30 ml) at 32° of 1-methylsulphinyl-1-methylthio-2-nitroethylene (906 mg). Evaporation of the reaction mixture gave an oil which was crystallised from isopropanol to give the title product (230 mg) m.p. 66°-67.5°.
Reaction SMILES: C(N(CC)CC)C.[C:8](#[N:11])[CH:9]=[CH2:10].[CH2:12]([O:14][C:15](=[O:30])[CH2:16][CH2:17][NH:18][CH2:19][C:20]1[C:23]2[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=2[CH:21]=1)[CH3:13]>C(O)C>[CH2:12]([O:14][C:15](=[O:30])[CH2:16][CH2:17][N:18]([CH2:10][CH2:9][C:8]#[N:11])[CH2:19][C:20]1[C:23]2[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=2[CH:21]=1)[CH3:13]
Reactant: C=CC#N
Reactant: CCOC(=O)CCNCC1=Cc2ccc(OC)cc21
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CCN(CCC#N)CC1=Cc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
10.5 g (0.1 mol) of triethylamine and 5.84 g (0.11 mol) of acrylonitrile are added to 30.16 g (0.1 mol) of 3-(5-methoxybenzocyclobuten-1-ylmethylamino)-propionic acid ethyl ester in 250 ml of ethanol and the whole is stirred at room temperature for 15 hours. The reaction mixture is then concentrated under a water-jet vacuum, and the residue is taken up in diethyl ether and washed neutral with ice-water. The ethereal solution is dried over potassium carbonate, filtered and concentrated by evaporation; 3-{N-(2-cyanoethyl)-N-[(5-methoxybenzocyclobuten-1-yl)methyl]-amino}propionic acid ethyl ester is obtained in the form of a yellow oil.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[NH:12][CH:13]=[C:14]([C:15]([OH:17])=O)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OCC)C>[C:19]1([NH:18][C:15]([C:14]2[C:10]3[C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[NH:3][C:2](=[O:1])[C:11]=3[NH:12][CH:13]=2)=[O:17])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccccc3c12
Solvent: CCOCC
Product: O=C(Nc1ccccc1)c1c[nH]c2c(=O)[nH]c3ccccc3c12
Yield: 45 %

Procedure:
This compound is prepared according to synthesis 79 from 75 mg (0.33 mmol) of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 75) and 33 μL (0.36 mmol) of aniline. After trituration in diethyl ether, 45 mg (45%) of N-(phenyl)-4-oxo-4,5-dihydro-3H -pyrrolo[2,3-c]quinoline-1-carboxamide is obtained in the form of a light brown solid.