Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26]([NH:28][S:29]([CH2:32][CH2:33][CH2:34]Cl)(=[O:31])=[O:30])=[O:27])=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>O1CCCC1>[C:1]1([C:7]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26]([NH:28][S:29]([CH2:32][CH2:33][CH2:34][N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)(=[O:31])=[O:30])=[O:27])=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(C=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1)NS(=O)(=O)CCCCl
Reactant: C1CCNCC1
Solvent: C1CCOC1
Product: O=C(C=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1)NS(=O)(=O)CCCN1CCCCC1

Procedure:
Prepared by coupling 2i and piperidine (15 eq)in tetrahydrofuran at reflux. The product was isolated as the HCL salt. Yield (70%); 1H NMR (d6-DMSO) δ 11.90 (br s, 1H), 7.53 (d, J=15.7 Hz, 1H), 7.34-7.10 (m, 12H), 6.88 (d, J=8.4 Hz, 2H), 6.70 (d, J=7.3 Hz, 1H), 6.55 (d, J=15.7 Hz, 1H), 3.52 (t, J=7.3 Hz, 2H), 3.09 (br, 2H), 2.77 (br m, 4H), 2.26 (br t, 2H), 2.08 (br, 4H), 1.71 (br, 5H); APcI m/z: 555 (M+H+).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:5][C@@H:4]1[C:6]1[N:11]=[CH:10][C:9]([C:12]([OH:15])([CH3:14])[CH3:13])=[CH:8][CH:7]=1.[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[C:19]([CH3:24])[N:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[Cl:16][C:17]1[N:18]=[C:19]([CH3:24])[N:20]=[C:21]([O:1][CH2:2][C@H:3]2[CH2:5][C@@H:4]2[C:6]2[N:11]=[CH:10][C:9]([C:12]([OH:15])([CH3:13])[CH3:14])=[CH:8][CH:7]=2)[CH:22]=1
Reactant: CC(C)(O)c1ccc([C@H]2C[C@@H]2CO)nc1
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: Cc1nc(Cl)cc(OC[C@H]2C[C@@H]2c2ccc(C(C)(C)O)cn2)n1
Yield: 27.7 %

Procedure:
A solution of compound 8-2 (135 mg, 0.652 mmol) and 4,6-dichloro-2-methylpyrimidine (106.3 mg, 0.65 mmol) in THF (3.0 mL) was treated with Cs2CO3 (281 mg, 0.86 mmol) and heated to reflux for 12 h. The reaction mixture was filtrated and the filtrate was concentrated and purified directly by gradient elution on silica gel (Petroleum ether:ethyl acetate=2:1-1:1) to afford the title compound as a colorless oil (60 mg, 28%). LRMS (ES) calculated M+H for C17H20ClN3O2: 334.12. Found: 334.1.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[C:5]2[N:6]([CH:11]=[C:12]([CH3:14])[N:13]=2)[N:7]=[C:8]([CH3:10])[CH:9]=1)[CH3:3].[CH2:15]([CH:17]([C:20]1[C:21]2[N:22]([C:27](I)=[C:28]([CH3:30])[N:29]=2)[N:23]=[C:24]([CH3:26])[CH:25]=1)[CH2:18][CH3:19])[CH3:16]>>[CH2:15]([CH:17]([C:20]1[C:21]2[N:22]([C:27]([C:11]3[N:6]4[N:7]=[C:8]([CH3:10])[CH:9]=[C:4]([CH:2]([CH3:1])[CH3:3])[C:5]4=[N:13][C:12]=3[CH3:14])=[C:28]([CH3:30])[N:29]=2)[N:23]=[C:24]([CH3:26])[CH:25]=1)[CH2:18][CH3:19])[CH3:16]
Reactant: Cc1cn2nc(C)cc(C(C)C)c2n1
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)nc4c(C(C)C)cc(C)nn34)c(C)nc12
Yield: 31.7 %

Procedure:
Using a procedure analogous to Example 16B, 8-(1-methylethyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.19 g, 1.01 mmol) and 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.40 g, 1.16 mmol) give the title compound (0.13 g, 0.32 mmol, 32%). 1H NMR (CDCl3): δ 0.92 (t, J=7.5 Hz, 6H), 1.43 (d, J=1.4 Hz, 3H), 1.45 (d, J=1.4 Hz, 3H), 1.80-1.93 (m, 4H), 2.43 (s, 3H), 2.44 (s, 3H), 2.47 (s, 3H), 2.48 (s, 3H), 3.36-3.44 (m, 1H), 3.74-3.82 (m, 1H), 6.69 (s, 1H), 6.75 (s, 1H) ppm. ES-MS (m/z): calcd for C24H32N6 (M+H)+: 405.6. found: 405.3.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[Si:9]([O:16][C@@H:17]1[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:19]([C:29]([O:31][CH3:32])=[O:30])[CH2:18]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].CI>C1COCC1.CCOCC>[Si:9]([O:16][C@@H:17]1[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:19]([CH3:2])([C:29]([O:31][CH3:32])=[O:30])[CH2:18]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:11]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CI
Product: COC(=O)C1(C)C[C@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 127.2 %

Procedure:
LDA (2M in Heptane/THF/ethylbenzene, 48.5 ml, 97 mmol) was mixed with 100 ml THF at −78° C. and stirred for 5 mins. (2S,4S)-1-tert-butyl 2-methyl 4-(tert-butyldimethylsilyloxy)pyrrolidine-1,2-dicarboxylate (14 g, 38.92 mmol) in 80 ml THF was added dropwise at −78° C. The mixture was stirred at −40° C. for 1 hr. Then the mixture was stirred at −78° C. for 10 mins. MeI (4.85 ml, 77.8 mmol) was slowly added and the mixture was stirred from −78° C. to r.t. overnight. The mixture was diluted with ether and quenched with 5% HCl. The organic layer was separated and washed with NaHCO3, brine, dried over MgSO4 and concentrated. 18.5 g of crude product as a diastereomeric mixture at C-2 was obtained.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12]OS(C3C=CC(C)=CC=3)(=O)=O)[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH2:28]([NH2:32])[CH2:29][CH2:30][CH3:31]>C(#N)C>[F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12][NH:32][CH2:28][CH2:29][CH2:30][CH3:31])[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:3]=1
Reactant: CCCCN
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CCCCNCC1COc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 42 using [5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), butan-1-amine (0.5 ml), ACN (2.5 ml). MS m/z (rel. intensity, 70 eV) 317 (M+, 2), 274 (7), 87 (6), 86 (bp), 70 (6).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[N:38]O)[NH2:37])=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:38]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[O:8])[CH2:10]3)[O:28][N:37]=2)=[CH:32][CH:31]=1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: NC(=NO)c1ccc(F)cc1
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3ccc(F)cc3)no2)C1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 34 mg (0.22 mmol, 1.1 eq.) of 4-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 55 mg (53% of theory)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([OH:19])[CH:15]=[CH:16][C:17]=1[Cl:18].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[Cl:18][C:17]1[CH:16]=[CH:15][C:14]([O:19][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)=[CH:13][C:12]=1[NH2:11]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Nc1cc(O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc([N+](=O)[O-])cn2)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.6 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (4.76 g, 30 mmol) and 3-amino-4-chlorophenol (4.31 g, 30 mmol) in N,N-dimethylformamide (15 mL) was added potassium carbonate (4.15 g, 30 mmol), and the mixture was stirred at room temperature for 16 hr. Ethyl acetate (80 mL) was added to the reaction mixture, and the mixture was washed successively with water (50 mL) and saturated brine (50 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residual solid was recrystallized from ethyl acetate (15 mL)/n-hexane (15 mL), and the precipitated crystals were collected by filtration, washed with diisopropyl ether (20 mL) and dried under reduced pressure to give the title compound (6.74 g, 85%) as brownish-red crystals.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([C:26]([N:28]2[CH2:33][CH2:32][N:31]([S:34]([CH3:37])(=[O:36])=[O:35])[CH2:30][CH2:29]2)=[O:27])=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[O:38]1[CH2:43][CH2:42][C:41](=O)[CH2:40][CH2:39]1>>[CH3:37][S:34]([N:31]1[CH2:30][CH2:29][N:28]([C:26]([C:21]2[NH:22][C:23]3[C:19]([CH:20]=2)=[CH:18][C:17]([C:15]([N:11]2[CH2:12][CH2:13][CH2:14][N:8]([CH:41]4[CH2:42][CH2:43][O:38][CH2:39][CH2:40]4)[CH2:9][CH2:10]2)=[O:16])=[CH:25][CH:24]=3)=[O:27])[CH2:33][CH2:32]1)(=[O:36])=[O:35]
Reactant: O=C1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(C)(=O)=O)CC4)cc3c2)CC1
Product: CS(=O)(=O)N1CCN(C(=O)c2cc3cc(C(=O)N4CCCN(C5CCOCC5)CC4)ccc3[nH]2)CC1

Procedure:
The title compound was synthesized in analogy to example 47, from 4-[2-(4-methanesulfonyl-piperazine-1-carbonyl)-1H-indole-5-carbonyl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester and tetrahydro-4H-pyran-4-one. Yellow gum. MS (m/z): 518.3 (M+H)+.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[O:9]=[C:10]1[N:17]2[CH:12]([CH:13]([CH3:20])[CH2:14][O:15][C:16]2([CH3:19])[CH3:18])[CH:11]1[CH3:21].[CH2:22]=[O:23].[Cl-].[Na+]>O1CCCC1.O>[O:23]=[C:22]1[N:17]2[CH:12]([CH:13]([CH3:20])[CH2:14][O:15][C:16]2([CH3:18])[CH3:19])[C:11]1([CH3:21])[CH2:10][OH:9]
Reactant: CC1COC(C)(C)N2C(=O)C(C)C12
Reactant: C=O
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC1COC(C)(C)N2C(=O)C(C)(CO)C12
Temperature: -78 °C
Reaction time: 0.03 h

Procedure:
To a solution of 1.1 equivalents of freshly prepared lithium diisopropylamide in anhydrous tetrahydrofuran under a nitrogen atmosphere at -78° is added a solution of 8-oxo-2,2,5,7-tetramethyl-3-oxa-1-azabicyclo[4.2.0]octane in anhydrous tetrahydrofuran which has been cooled to -78° C. After two minutes, the resulting lihtium enolate is treated with excess formaldehyde, introduced as a gas just above the surface of the stirred solution. The solution is stirred for 30 minutes at -78° and then poured into water. The aqueous phase is saturated with sodium chloride and extracted with ethyl acetate. The combined ethyl acetate solutions are dried over magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure to give the crude product. Purification by chromatography on silica gel using ethyl acetate/benzene gives 8-oxo-2,2,5,7-tetramethyl-7-(hydroxymethyl)-3-oxa-1-azabicyclo[4.2.0]-octane.
Reaction SMILES: [CH2:1]([C@H:8]([NH:19][C:20](=[O:43])[O:21][NH:22][C:23](=[O:42])[C@@H:24]([NH:29][C:30]([C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1)=[O:31])[CH2:25][C:26]([NH2:28])=[O:27])[C@H:9]([OH:18])[CH2:10][NH:11][O:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:63]1[C:71]2[C:66](=[CH:67][CH:68]=[C:69]([S:72](Cl)(=[O:74])=[O:73])[CH:70]=2)[CH:65]=[N:64]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:1]([C@H:8]([NH:19][C:20](=[O:43])[O:21][NH:22][C:23](=[O:42])[C@@H:24]([NH:29][C:30]([C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1)=[O:31])[CH2:25][C:26]([NH2:28])=[O:27])[C@H:9]([OH:18])[CH2:10][N:11]([O:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17]1)[S:72]([C:69]1[CH:70]=[C:71]2[C:66]([CH:65]=[N:64][NH:63]2)=[CH:67][CH:68]=1)(=[O:74])=[O:73])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2c1
Reactant: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)NOC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CNOC1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)NOC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN(OC1CCCC1)S(=O)(=O)c1ccc2cn[nH]c2c1
Reaction time: 24 h

Procedure:
(2S)-4-Amino-4-oxo-2-[(2-quinolinylcarbonyl)-amino]butanamido N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)-aminol-2-hydroxypropylcarbamate (Step 1, Example 51), (44 mg, 0.0825 mmol), 1-trityl-1H-indazole-6-sulfonyl chloride (38 mg, 0.0825 mmol), and anhydrous diisopropylethylamine (0.05 mL, 0.280 mmol) were combined in anhydrous tetrahydrofuran (3 mL) in a 25 mL round bottomed flask under nitrogen. The reaction was stirred for 24 hours and concentrated in vacuc. Ethyl acetate (30 mL) and water (10 mL) were added and the layers were separated. The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuc. The compound was deprotected as described in Example 57 and purified by preparative silica gel TLC using 90:10 chloroform: methanol as an eluent to provide the desired product as a white film (9 mg, 0.013 mmol, 15%). 1HNMR (d6-DMSO) 6:8.84 (d, J=8.5 Hz, 1H), 8.61 (d, J=8.5 Hz, 1H), 8.31-6.95 (m, 13H), 5.24 (d, J=6.6 Hz, 1H), 4.81-4.72 (m, 2H), 3.97 (bs, 1H), 3.68 (bs, 1H), 3.40-1.20 (m, 15H). MS(ES): 714 (M+1), 712 (M-1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[OH-].[K+].[CH2:13]([OH:15])[CH3:14]>[Cl-].[NH4+]>[CH2:13]([O:15][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)[CH3:14]
Reactant: CCO
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Product: CCOc1ccc([N+](=O)[O-])cn1
Reaction time: 1 h

Procedure:
2-Chloro-5-nitropyridine was added to a homogeneous solution of potassium hydroxide (3.93 g, 70 mmol) in ethanol (35 mL) at ambient temperature. The reaction mixture was stirred for 1 h, then diluted with saturated aqueous ammonium chloride and cooled in an ice bath. The precipitate was collected, rinsed with water and dried to give 3.60 g of 2-ethoxy-5-nitropyridine as a beige solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH:17]([C:19]([CH3:21])=[O:20])=[CH2:18]>>[CH:11]1([C:5]2[CH:6]=[CH:7][C:8]([CH2:18][CH2:17][C:19](=[O:20])[CH3:21])=[CH:9][CH:10]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: c1ccc(C2CCCCC2)cc1
Reactant: C=CC(C)=O
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)CCc1ccc(C2CCCCC2)cc1
Reaction time: 8 h

Procedure:
To a stirred solution of aluminium chloride (0.15 mole) in cyclohexylbenzene (0.5 mole) at 10°-15° C. was added dropwise methyl vinyl ketone. The resulting mixture was left overnight at room temperature and worked up as above. The crude ketone was purified by distillation, b.p. 150-60 (2 mm), followed by column chromatography using silica as support and petrol/ethyl acetate as eluants.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].S(=O)(=O)(O)O.[F:14][C:15](I)([F:17])[F:16].OO>[Fe].CS(C)=O>[F:14][C:15]([F:17])([F:16])[C:7]1[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][CH:8]=1
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: FC(F)(F)I
Agent: [Fe]
Agent: O=S(=O)(O)O
Agent: OO
Solvent: CS(C)=O
Product: O=c1[nH]cc(C(F)(F)F)c(=O)[nH]1
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 32 %

Procedure:
0.11 g (1.0 mmol) of uracil and 0.028 g (0.5 mmol) of iron powder were weighed and placed in a 50 ml two-neck flask equipped with a magnetic rotor and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 2.0 ml of dimethyl sulfoxide, 2.0 ml of a 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 ml of a 3.0 mol/l dimethyl sulfoxide solution of trifluoromethyl iodide and 0.2 ml of a 30% hydrogen peroxide aqueous solution. The mixture was stirred at 40 to 50° C. for 20 minutes and then the resulting solution was cooled to room temperature. Formation of 5-trifluoromethyluracil (19F-NMR yield: 32%) was confirmed in the same manner as in Example 1.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[CH:5][N:4]=[C:3]1[C:8](=[NH:10])[NH2:9].C(O[C@@H:15]1[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:32])[CH3:31])[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:16]1[O:17][C:18](=[O:20])[CH3:19])(=O)C.FC(F)(F)C(O)=O.O>C[Si](C)(C)N[Si](C)(C)C.C(#N)C.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>[C:23]([O:22][C@H:21]1[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:15]([N:7]2[CH:6]=[CH:5][N:4]=[C:3]([C:8]([NH2:9])=[NH:10])[C:2]2=[O:1])[O:27][C@@H:26]1[CH2:28][O:29][C:30](=[O:32])[CH3:31])(=[O:25])[CH3:24]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: N=C(N)c1ncc[nH]c1=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](n2ccnc(C(=N)N)c2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.4 %

Procedure:
In 2.0 mL of 1,1,1,3,3,3-hexamethyldisilazane were suspended 0.20 g of 3-oxo-3,4-dihydro-2-pyrazinecarboximidamide and 10 mg of ammonium sulfate. Under a stream of nitrogen gas, the suspension was heated under reflux for 10 minutes. After adding 9.0 mg of ammonium sulfate, the mixture was heated under reflux for an additional 2 hours. The reaction mixture was allowed to cool, and the solvent was removed under reduced pressure. The residue thus obtained was dissolved in 4.0 mL of acetonitrile, 0.46 g of β-D-ribofuranose-1,2,3,5-tetraacetate and 0.34 mL of stannic (IV) chloride were successively added, and the mixture thus obtained was stirred at room temperature for 3 hours. Then, 10 μL of trifluoroacetic acid and 1.0 mL of water were added to the reaction mixture, and the solvent was removed under reduced pressure. Further, the same reaction as above was repeated by using 0.05 g of 3-oxo-3,4-dihydro-2-pyrazinecarboximidamide. The reaction mixture thus obtained was united with the reaction mixture obtained above, and the product was purified by reversed phase silica gel column chromatography [eluent: acetonitrile:water=1:4] to obtain 0.34 g of (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-[3-[amino(imino)methyl]-2-oxo-1(2H)-pyrazinyl]tetrahydro-3-furanyl acetate as a light yellow-colored solid product.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:4]=1.[N:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[C:26]=[O:27]>C(Cl)Cl>[C:28]([NH:25][C:26]([NH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:4]=1)=[O:27])([CH3:31])([CH3:30])[CH3:29]
Reactant: NCc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12
Reactant: CC(C)(C)N=C=O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)NCc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
A mixture of the product from Example 42 (13.8 mg, 0.040 mmol) and 2-isocyanato-2-methylpropane (5.2 μL, 0.044 mmol) in DCM (0.4 mL) was stirred at room temperature for 2 hours, concentrated, and chromatographed (5% MeOH/DCM) to give 12.1 mg of the title compound as a white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 11.58-11.61 (bs, 1H), 8.32 (dd, J=7.8, 1.4 Hz, 1H), 8.14 (d, J=8.0 Hz, 1H), 7.98 (ddd, J=8.0, 7.2, 1.5 Hz, 1H), 7.90 (ddd, J=7.9, 7.2, 1.3 Hz, 1H), 7.41 (s, 4H), 6.19 (t, J=5.8 Hz, 1H), 5.81 (s, 1H), 4.50 (d, J=5.8 Hz, 2H), 3.68 (s, 2H), 1.22 (s, 9H); MS (ESI−) M/Z 440 (M−H)−, 486 (M+COOH)−.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([C@@H:17]4[CH2:21][CH2:20][CH2:19][N:18]4[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH:14][C:13]=3[CH:29]=2)O1.[Br:31][C:32]1[CH:45]=[CH:44][C:43]2[C:42]3[C:37](=[CH:38][C:39](Br)=[CH:40][CH:41]=3)[CH2:36][CH2:35][C:34]=2[CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(COC)OC>[Br:31][C:32]1[CH:33]=[C:34]2[C:43]([C:42]3[CH:41]=[CH:40][C:39]([C:9]4[CH:10]=[CH:11][C:12]5[N:16]=[C:15]([C@@H:17]6[CH2:21][CH2:20][CH2:19][N:18]6[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[NH:14][C:13]=5[CH:29]=4)=[CH:38][C:37]=3[CH2:36][CH2:35]2)=[CH:44][CH:45]=1
Reactant: Brc1ccc2c(c1)CCc1cc(Br)ccc1-2
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc(-c3ccc4c(c3)CCc3cc(Br)ccc3-4)cc2[nH]1
Temperature: 85 °C
Reaction time: 16 h
Yield: 59.2 %

Procedure:
A mixture of ((S)-tert-butyl 2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (1.49 g, 3.6 mmol), 2,7-dibromo-9,10-dihydrophenanthrene (6.09 g, 18.0 mmol), 2M aqueous potassium carbonate solution (9 mL, 18.0 mmol), tetrakis(triphenylphosphine)palladium(0) (209 mg, 0.18 mmol) and dimethoxyethane (36 mL) was degassed with a stream of argon for twenty minutes. The reaction was heated to 85° C. After 16 hours, the reaction was cooled to room temperature and diluted with ethyl acetate. The organic phase was washed with saturated aqueous NaHCO3 solution and brine, dried (Na2SO4) and concentrated. The crude material was purified by flash column chromatography to yield (S)-tert-butyl 2-(6-(7-bromo-9,10-dihydro-phenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)-pyrrolidine-1-carboxylate (1.16 g, 59%).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl-].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][Zn+])=[CH:17][CH:16]=1.O>O1CCCC1.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>[Cl:12][C:9]1[CH:10]=[N:11][C:2]([CH2:19][C:18]2[CH:21]=[CH:22][C:15]([F:14])=[CH:16][CH:17]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: Fc1ccc(C[Zn+])cc1
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)cnc1Cc1ccc(F)cc1
Temperature: 60 °C
Yield: 88 %

Procedure:
To a stirred solution of methyl 2,5-dichloronicotinate (Journal of Chemical and Engineering Data 1981, 26, 332, 350 mg, 1.70 mmol) and tetrakis(triphenylphosphine)palladium(0) (196 mg, 0.17 mmol) in tetrahydrofuran (6 mL) was added a 0.5 M solution of 4-fluorobenzylzinc chloride in tetrahydrofuran (4.08 mL, 2.04 mmol) at 0° C. under nitrogen. The resulting mixture was heated at 60° C. for 16 h. The mixture was poured into water (50 mL) and the aqueous mixture was extracted with ethyl acetate (100 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (6/1) to afford 416 mg (88%) of the title compounds as colorless oil: 1H-NMR (CDCl3) δ 8.64 (1H, d, J=2.6 Hz), 8.17 (1H, d, J=2.6 Hz), 7.24–7.20 (2H, m), 6.96–6.90 (2H, m), 4.50 (2H, s), 3.89 (3H, s).
Reaction SMILES: [Na].[N+](C(C)C)([O-])=[O:3].Br[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[N:20]=[C:19]([C:21]#[N:22])[CH:18]=[N:17]2)=[CH:12][CH:11]=1>C(O)C>[CH:9]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[N:20]=[C:19]([C:21]#[N:22])[CH:18]=[N:17]2)=[CH:12][CH:11]=1)=[O:3]
Reactant: N#Cc1cnn(-c2ccc(CBr)cc2)n1
Reactant: CC(C)[N+](=O)[O-]
Agent: [Na]
Solvent: CCO
Product: N#Cc1cnn(-c2ccc(C=O)cc2)n1

Procedure:
4.6 g of sodium are dissolved in 300 ml of absolute ethanol, with stirring and whilst passing a vigorous stream of nitrogen over the mixture. 23.2 g of 2-nitropropane (purity: about 95%) are then added dropwise at 21° C. in the course of 5 minutes and the reaction mixture is stirred at 20° to 25° C. for a further 2 hours. 52.6 g of 2-(p-bromomethyl-phenyl)-4-cyano-2H-1,2,3-triazole are then introduced and the reaction mixture is slowly heated up to the reflux temperature and refluxed for 2 hours. After cooling, the product which has crystallised out is filtered off with suction, stirred with 500 ml of water, again filtered off with suction and washed well with about 2 liters of water. This gives 21.8 g of 2-(p-formyl-phenyl)-4-cyano-2H-1,2,3-triazole with a melting point of 148° to 150° C.