Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C@@H:3]([OH:27])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:15]2[CH:26]=[CH:25][C:18]([O:19][CH2:20][C@H:21]([OH:24])[CH2:22][OH:23])=[CH:17][CH:16]=2)([CH3:14])[CH3:13])=[CH:8][CH:7]=1.[C:28]1(=[O:34])[O:33][C:31](=[O:32])[CH2:30][CH2:29]1>N1C=CC=CC=1>[C:28]([OH:33])(=[O:34])[CH2:29][CH2:30][C:31]([OH:5])=[O:32].[C:28]([OH:33])(=[O:34])[CH2:29][CH2:30][C:31]([OH:5])=[O:32].[C:28]([OH:33])(=[O:34])[CH2:29][CH2:30][C:31]([OH:5])=[O:32].[Cl:1][CH2:2][C@@H:3]([OH:27])[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([C:15]2[CH:16]=[CH:17][C:18]([O:19][CH2:20][C@@H:21]([OH:24])[CH2:22][OH:23])=[CH:25][CH:26]=2)([CH3:14])[CH3:13])=[CH:10][CH:11]=1
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)(c1ccc(OC[C@H](O)CO)cc1)c1ccc(OC[C@H](O)CCl)cc1
Solvent: c1ccncc1
Product: CC(C)(c1ccc(OC[C@H](O)CCl)cc1)c1ccc(OC[C@@H](O)CO)cc1
Product: O=C(O)CCC(=O)O
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a solution of (R)-3-(4-(2-(4-((S)-3-chloro-2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)propane-1,2-diol (700 mg, 1.77 mmol) in anhydrous pyridine (6.0 ml) were added succinic anhydride (710 mg, 7.10 mmol) and the mixture was heated at 70° C. After 3 h, the reaction mixture was quenched with an aqueous solution of sodium chloride and stirred for 15 min, and the resulting mixture was extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, and filtered. Solvents were evaporated, and the resulting crude material was purified by silica gel flash chromatography (eluent: 5% to 30% methanol in dichloromethane) to provide the title compound.
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:32]=[CH:31][C:13]([O:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)=[CH:12][CH:11]=1)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[ClH:1].[OH:9][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=3)[CH2:19][CH2:18]2)=[CH:31][CH:32]=1
Reactant: [H][H]
Reactant: Cc1ccc(CC2CCN(CCOc3ccc(OCc4ccccc4)cc3)CC2)cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(CC2CCN(CCOc3ccc(O)cc3)CC2)cc1
Yield: 70.3 %

Procedure:
A mixture of 1-[2-(4-benzyloxyphenoxy)ethyl]-4-(4-methylbenzyl)piperidine hydrochloride (250 mg, 0.55 mmol) in 25 mL of ethanol with 60 mg of 20% Pd(OH)2 was hydrogenated at 30 psi of hydrogen to give 140 mg (88%) of the title compound, mp 198-200° C. 1H NMR (CD3OD) 1.6 (m, 2 H), 1.881-1.923 (m, 3 H), 2.288 (s, 3 H), 2.572 (d, J=6.6 Hz, 2 H), 3.06 (m, 2 H), 3.473 (m, 2 H), 3.61 (m, 2 H), 4.243 (t, J=5.1 Hz, 2 H), 6.709 (dd, J1 =2.4 Hz, J2 =6.6 Hz, 2 H), 6.830 (dd, J1 =2.4 Hz, J2 =6.6 Hz, 2 H), 7.703 (m, 4 H). Anal. Calcd for C21H28ClNO2.0.5H2O: C, 68.00; H, 7.88; N, 3.78. Found: C, 68.14; H, 7.65; N. 3.72.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH2:9][O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[N+:12]([O-])([OH:14])=[O:13]>C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3]1[C:11]2[O:10][CH2:9][O:8][C:7]=2[CH:6]=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cccc2c1OCO2
Solvent: CC(=O)OC(C)=O
Product: COc1cc([N+](=O)[O-])cc2c1OCO2
Temperature: 25 °C
Yield: 46 %

Procedure:
4-Methoxy-benzo[1,3]dioxole (2.03 g, 13.34 mmole) was dissolved in acetic anhydride (20 mL) and cooled in an ice bath while stirring. Nitric acid (1.5 mL) was added dropwise with an addition funnel over 30 minutes. The ice bath was removed and the mixture was stirred overnight allowing the reaction to heat up to room temperature. The mixture was poured into ice water and the product crashed out and was filtered and washed with water. The precipitate was dried under vacuum in a dessicator yielding (1.21 g, 46% yield) of 4-methoxy-6-nitro-benzo[1,3]dioxole. NMR-DMSO-d6: 7.63 (s, 1H), 7.52 (s, 1H), 6.25 (s, 2H), 3.95 (s, 3H)
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH:8]=2)[CH2:5][CH:4]([C:24]([NH:26][CH:27]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH2:28][C:29]([OH:31])=O)=[O:25])[CH2:3]1.[C:38]1([S:44]([NH2:47])(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([NH:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH:8]=2)[CH2:5][CH:4]([C:24]([NH:26][CH:27]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH2:28][C:29]([NH:47][S:44]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:46])=[O:45])=[O:31])=[O:25])[CH2:3]1
Reactant: O=C(O)CC(NC(=O)C1CC(=O)N(c2cccc(NC(=O)NCc3ccccc3)c2)C1)c1cccnc1
Reactant: NS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CC(NC(=O)C1CC(=O)N(c2cccc(NC(=O)NCc3ccccc3)c2)C1)c1cccnc1)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A suspension of 3-{(5-oxo-1-(3-{(benzylamino)carbonylamino}phenyl)pyrrolidin-3-yl)carbonylamino}-3-(3-pyridyl)propanoic acid (60 mg, 0.11 mmol), benzenesulfonamide (Aldrich, 18 mg, 0.11 mmol), 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloride (22 mg, 0.11 mmol), and dimethyl-4-pyridylamine (Aldrich, 0.22 mmol) in CH2Cl2 (5 mL) was stirred at room temperature for 2 days. A white solid was filtered and further purified by preparative HPLC. The title compound was obtained as a white solid. MS (ES+): 643 (M+H)+; (ES−): 641 (M−H)−.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:3]=1.[CH3:19][C:20]1[O:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)=[CH:23][N:24]=1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:4]2[N:3]=[C:2]([NH:31][C:28]3[CH:27]=[CH:26][C:25]([C:22]4[O:21][C:20]([CH3:19])=[N:24][CH:23]=4)=[CH:30][CH:29]=3)[N:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=2)=[CH:13][CH:14]=1
Reactant: CC(C)(O)c1cc(-c2ccc(Cl)cc2)nc(Cl)n1
Reactant: Cc1ncc(-c2ccc(N)cc2)o1
Product: Cc1ncc(-c2ccc(Nc3nc(-c4ccc(Cl)cc4)cc(C(C)(C)O)n3)cc2)o1
Yield: 22.2 %

Procedure:
Using in analogous manner the procedure described in example 1e), 2-[2-chloro-6-(4-chloro-phenyl)-pyrimidin-4-yl]-propan-2-ol (112 mg, 0.3 mmol) was reacted with 4-(2-methyl-oxazol-5-yl)-phenylamine (61 mg, 0.3 mmol) to give the title compound as light yellow solid (28 mg, 22%). MS ISP (m/e): 421.1 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.04, 7.74, 7.63 and 7.50 (4 d, 4×2H), 7.20 (s, 1H), 7.23 (s, 1H), 7.15 (s, 1H), 4.01 (s, 1H), 2.53 (s, 3H), 1.61 (s, 6H).
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8](Cl)[C:7]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:6][C:3]=1[C:4]#[N:5].[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-:22].[Na+]>CN(C)C=O>[O:21]([C:2]1[CH:9]=[C:8]([O:22][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:3]=2)[C:7]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:6][C:3]=1[C:4]#[N:5])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Oc1ccccc1
Reactant: [OH-]
Reactant: N#Cc1cc(S(N)(=O)=O)c(Cl)cc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(S(N)(=O)=O)c(Oc2ccccc2)cc1Oc1ccccc1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
A mixture of 251 g of 2,4-dichloro-5-sulfamoyl-benzonitrile (1.0 mol), 400 ml of dimethylformamide, 200 g of phenol and 80 g of sodium hydroxide was stirred for 3 hours at 130° C. The mixture was then allowed to cool to about 90° C and when its viscosity was low and it was turbid from precipitated NaCl, it was introduced into 10 l of water. After having been allowed to stand for 1 hour at room temperature, the light grey crystallized precipitate was suction-filtered, washed several times with water, and the product still moist after filtration was then recrystallized from isopropanol. The product was first dried in the air and then on a steam bath until its weight remained constant. The colorless crystals thus obtained still contained one mol-equivalent of isopropanol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C@:4]([CH2:8][OH:9])([CH3:7])[CH:5]=[CH2:6].[F:11][C:12]([F:20])(S(F)(=O)=O)C(O)=O.O>C(#N)C.[Cu]I>[CH3:1][O:2][C:3](=[O:10])[C@:4]([CH2:8][O:9][CH:12]([F:20])[F:11])([CH3:7])[CH:5]=[CH2:6]
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: C=C[C@](C)(CO)C(=O)OC
Agent: [Cu]I
Solvent: CC#N
Solvent: O
Product: C=C[C@](C)(COC(F)F)C(=O)OC
Temperature: 25 °C
Yield: 50.2 %

Procedure:
A solution of (R)-2-hydroxymethyl-2-methyl-but-3-enoic acid methyl ester (288 mg, 2.0 mmol) in acetonitrile (8 mL) was stirred at room temperature under nitrogen. Copper(I) iodide (80 mg, 0.4 mmol) was added followed by difluoro-fluorosulfonyl-acetic acid (356 mg, 0.2 mL, 2.0 mmol) and the reaction mixture was heated at reflux for 30 minutes. The reaction mixture was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of pentane/diethyl ether 10:1 to 5:1 to afford the title compound (195 mg, 50%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 1.40 (s, 3H), 3.75 (s, 3H), 3.86 (d, J=9.4 Hz, 1H), 4.10 (d, J=9.4 Hz, 1H), 5.24 (d, J=17.4 Hz, 1H), 5.24 (dd, J=10.9 Hz, 1H), 5.95 (dd, J=17.4, 10.9 Hz, 1H), 6.22 (t, J=74.3 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6])([O-:3])=[O:2].[I:12]I>C(Cl)(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[I:12][C:7]1[CH:8]=[CH:9][C:10]([OH:11])=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[OH:6]
Reactant: O=[N+]([O-])c1c(O)cccc1O
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1c(O)ccc(I)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A mixture of 1 g (6.4 mmol) of 2-nitroresorcinol, 1.42 g (6.4 mmol) of silver trifluoroacetate and 1.64 g (6.4 mmol) of iodine in 25 mL of chloroform was stirred overnight at room temperature. The reaction mixture was filtered through celite, washed with 20 mL of dichloromethane. The combined filtrate was washed with 10% aqueous sodium metabisulfite, water, brine and dried over anhydrous magnesium sulfate, evaporated to dryness to give 1.6 g of crude 4-iodo-2-nitroresorcinol [H11 NMR (CDCl3) 6.52 (d, 1H, CH, J=8.9 Hz); 7.85 (d, 1H, CH, J=8.9 Hz); 10.67 (s, 1H, OH); 11.43 (s, 1H, OH)] which was used in the next step without further purification. To a mixture of above product in 10 mL of anhydrous dimethylformamide 1.77 g (12.8 mmol) of anhydrous potassium carbonate was added at room temperature followed by 3 mL (48 mmol) of methyl iodide. After stirring overnight at room temperature resulting mixture was diluted to 150 mL with ethyl acetate, washed with water (3×15 mL) brine and dried over anhydrous magnesium sulfate, filtered off and filtrate evaporated to dryness to give 1.6 g of crude product, which was purified by flash column chromatography (silica gel hexane dichloromethane 7:3) to give 1.1 g (56%) of the title compound as a colourless crystals. H1 NMR (CDCl3) 3.87 (s, 3H, OMe); 3.91 (s, 1H, OMe); 6.6 (d, 1H, CH, J=8.9 Hz); 7.75 (d, 1H, CH, J=8.9 Hz).
Reaction SMILES: [CH3:1][S:2]([N:5]([CH3:29])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:20]2[C:15]([CH:16]=[N:17][C:18](OS(C(F)(F)F)(=O)=O)=[N:19]2)=[CH:14][CH:13]=1)(=[O:4])=[O:3].C(N(CC)C(C)C)(C)C.[CH3:39][O:40][C:41]1[CH:46]=[C:45]([CH2:47][N:48]2[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]2)[CH:44]=[CH:43][C:42]=1[NH2:55].COCC(O)C>>[CH3:39][O:40][C:41]1[CH:46]=[C:45]([CH2:47][N:48]2[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]2)[CH:44]=[CH:43][C:42]=1[NH:55][C:18]1[N:17]=[CH:16][C:15]2=[CH:14][CH:13]=[C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]([CH3:29])[S:2]([CH3:1])(=[O:4])=[O:3])[N:20]2[N:19]=1
Reactant: CN(c1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12)S(C)(=O)=O
Reactant: COc1cc(CN2CCN(C)CC2)ccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1cc(CN2CCN(C)CC2)ccc1Nc1ncc2ccc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Temperature: 120 °C
Yield: 30 %

Procedure:
Into a 8-dram vial, Trifluoro-methanesulfonic acid 7-[2-(methanesulfonyl-methyl-amino)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (89 mg, 0.20 mmol), N,N-Diisopropylethylamine (0.0757 mL, 0.435 mmol), 2-Methoxy-4-(4-methyl-piperazin-1-ylmethyl)-phenylamine and 1-Methoxy-2-propanol (0.71 mL) were added. The reaction mixture was heated at 120° C. for 6 hours. The solvent was removed under vacuum. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in CAN. The collected fraction afforded N-(2-{2-[2-Methoxy-4-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-phenyl)-N-methyl-methanesulfonamide as a yellow solid (32 mg, 30%). LCMS (E/I+) 536.16 (M+H). NMR 1H (DMSO-d6)-8.99 (s, 1H), 8.04 (d, 1H, J=8.09 Hz), 7.95-8.01 (m, 1H), 7.79 (s, 1H), 7.62-7.70 (m, 1H), 7.51-7.59 (m, 2H), 7.06 (s, 1H), 7.02 (d, 1H, J=4.66 Hz), 7.00 (d, 1H, J=4.66 Hz), 6.86 (d, 1H, J=8.22 Hz), 3.88 (s, 3H), 3.20-3.80 (m, 10H), 3.08 (s, 3H), 2.88 (s, 3H), 2.78 (s, 3H).
Reaction SMILES: [CH3:1][C@@:2]1([CH2:14][OH:15])[O:7][C:6]2=[N:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][N:5]2[CH2:4][CH2:3]1.[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1.[H-].[Na+]>>[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][O:15][CH2:14][C@:2]2([CH3:1])[O:7][C:6]3=[N:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][N:5]3[CH2:4][CH2:3]2)=[CH:19][CH:18]=1
Reactant: C[C@]1(CO)CCn2cc([N+](=O)[O-])nc2O1
Reactant: BrCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Product: C[C@]1(COCc2ccc(Br)cc2)CCn2cc([N+](=O)[O-])nc2O1
Yield: 57 %

Procedure:
Alkylation of (R)-alcohol 159 with 4-bromobenzyl bromide (1.3 equiv.) and NaH (1.5 equiv.) as in Example 2UU above for 3 h, followed by chromatography of the product on silica gel, eluting with CH2Cl2 (foreruns) and then with 1% EtOAc/CH2Cl2, gave (7R)-7-{[(4-bromobenzyl)oxy]methyl}-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (160) (349 mg, 57%) as a white solid: mp (CH2Cl2/hexane) 157-159° C.; 1H NMR (CDCl3) δ 7.46 (dt, J=8.3, 2.0 Hz, 2H), 7.39 (s, 1H), 7.12 (br d, J=8.3 Hz, 2H), 4.50 (s, 2H), 4.09 (ddd, J=12.5, 6.9, 6.0 Hz, 1H), 4.01 (ddd, J=12.5, 7.0, 6.0 Hz, 1H), 3.62 (d, J=10.2 Hz, 1H), 3.58 (d, J=10.2 Hz, 1H), 2.37 (ddd, J=14.4, 7.0, 6.0 Hz, 1H), 2.10 (ddd, J=14.4, 6.9, 6.1 Hz, 1H), 1.46 (s, 3H); [α]D27 30.0° (c 1.00, CHCl3); HRFABMS calcd for C15H17BrN3O4 m/z [M+H]+ 384.0382, 382.0402. found 384.0385, 382.0398.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](N3C=CN=C3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[OH:40].CN(C)C=O>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:40][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[Cl:33])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Reactant: Oc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Oc1ccccc1Cl)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 3.0 g (8.2 mmol) of 1-[[(S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[ 2,1-c][1,4]benzodiazepin-1-yl]carbonyl]imidazole, 1.59 g (11.5 mmol) of powdered potassium carbonate, 1.3 ml (11.5 mmol) of 2-chlorophenol and 20 ml of dry dimethylformamide is stirred at room temperature for 5 days, then poured into 60 ml of water and extracted three times with methylene chloride. The organic extracts are washed twice with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The crude product is chromatographed on silica gel, the elution being carried out successively with ethyl acetate/n-hexane (1:1), ethyl acetate/n-hexane (3:2) and ethyl acetate/n-hexane (7:3). After recrystallization from ethyl acetate, there is obtained o-chlorophenyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 214°-215°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:22])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]2[S:17][C:16]([CH:18]=O)=[CH:15][CH:14]=2)=[C:7]([O:20][CH3:21])[CH:6]=1.[C:23]([C:25]1[C:26](=[C:41]([C:44]#[N:45])[C:42]#[N:43])[O:27][C:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:31]([F:34])([F:33])[F:32])[C:29]=1[CH3:30])#[N:24]>C(O)C.C1COCC1>[C:23]([C:25]1[C:26](=[C:41]([C:44]#[N:45])[C:42]#[N:43])[O:27][C:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:31]([F:34])([F:32])[F:33])[C:29]=1[CH:30]=[CH:18][C:16]1[S:17][C:13]([CH:12]=[CH:11][C:8]2[CH:9]=[CH:10][C:5]([N:4]([CH2:3][CH2:2][OH:1])[CH3:22])=[CH:6][C:7]=2[O:20][CH3:21])=[CH:14][CH:15]=1)#[N:24]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(c1ccccc1)C(F)(F)F
Reactant: COc1cc(N(C)CCO)ccc1C=Cc1ccc(C=O)s1
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(N(C)CCO)ccc1C=Cc1ccc(C=CC2=C(C#N)C(=C(C#N)C#N)OC2(c2ccccc2)C(F)(F)F)s1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
In a mixed solvent of ethanol (15 ml) and THF (5 ml) were dissolved 5-(2-{4-[(2-hydroxyethyl) methylamino]-2-methoxyphenyl}vinyl)thiophene-2-carbaldehyde (0.5 g, 1.58 mmol) and 2-(3-cyano-4-methyl-5-phenyl-5-trifluoromethyl-5H-furan-2-ylidene)malononitrile (0.50 g, 1.58 mmol). The mixture was stirred at room temperature for 18 hours and further at 50° C. for 3 hours. The mixture was cooled and the solid was collected. The solid was washed with cold ethanol (40 ml) 3 times to give a reddish brown crystal (yield: 0.91 g (93.8%)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([Cl:15])[CH:14]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[NH2:11].CCN(CC)CC.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[Cl:15][C:13]1[CH:12]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:14]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[NH:11][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1nccn1Cc1cc(Cl)cc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1nccn1Cc1cc(Cl)cc(Cl)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
1-(3,5-dichloro-benzyl)-1H-imidazol-2-ylamine was dissolved in CH2Cl2 and Et3N was added followed by benzoyl chloride. The reaction mixture was stirred at room temperature for 2 h and washed with 1N HCl, saturated NaHCO3 and water. The organic phase was dried over Na2SO4 and concentrated. The residue was purified by silica gel prep TLC using 95:5 CH2Cl2:MeOH to afford N-[1-(3,5-dichloro-benzyl)-1H-imidazol-2-yl]-benzamide (40 mg, 56%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10](=[O:12])[C:9]([O:13][CH3:14])=[CH:8][C:7](=[O:15])[C:6]=2[C:5]([OH:16])=[C:4]2[C:17](=[O:37])[C@:18]3([C:32]4[C:31]([OH:33])=[C:30]5[C:25]([CH:26]=[C:27]([CH:35]=O)[NH:28][C:29]5=[O:34])=[CH:24][C:23]=4[CH2:22][CH2:21]3)[C:19](=[O:20])[C:3]=12.[Cl-].[CH3:39][O:40][NH3+:41].N1C=CC=CC=1.O>CN(C=O)C>[CH3:39][O:40][N:41]=[CH:35][C:27]1[NH:28][C:29](=[O:34])[C:30]2[C:25]([CH:26]=1)=[CH:24][C:23]1[CH2:22][CH2:21][C@@:18]3([C:17](=[O:37])[C:4]4=[C:5]([OH:16])[C:6]5[C:7](=[O:15])[CH:8]=[C:9]([O:13][CH3:14])[C:10](=[O:12])[C:11]=5[C:2]([OH:1])=[C:3]4[C:19]3=[O:20])[C:32]=1[C:31]=2[OH:33]
Reactant: COC1=CC(=O)c2c(O)c3c(c(O)c2C1=O)C(=O)[C@]1(CCc2cc4cc(C=O)[nH]c(=O)c4c(O)c21)C3=O
Reactant: CO[NH3+]
Agent: [Cl-]
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CON=Cc1cc2cc3c(c(O)c2c(=O)[nH]1)[C@@]1(CC3)C(=O)c2c(O)c3c(c(O)c2C1=O)C(=O)C(OC)=CC3=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ten (10) mg (19.4 μmol) fredericamycin aldehyde (4) are dissolved in 2 mL DMF. After addition of 3.4 mg (40.7 μmol) O-methylhydroxylammonium chloride and 3.2 μl pyridine, the reaction mixture is stirred for 2 h at room temperature. Then, it is added to 100 ml water, and the supernatant is sucked off from the red precipitate (HPLC clean).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[C:8]([S:13][C:14]2[CH:15]=[C:16]([O:22][C:23]3[C:24]([CH3:29])=[N:25][CH:26]=[CH:27][CH:28]=3)[C:17]([C:20]#[N:21])=[N:18][CH:19]=2)=[N:9][CH:10]=[CH:11][CH:12]=1.[OH-:30].[Na+]>>[CH3:6][C:7]1[C:8]([S:13][C:14]2[CH:15]=[C:16]([O:22][C:23]3[C:24]([CH3:29])=[N:25][CH:26]=[CH:27][CH:28]=3)[C:17]([C:20]([NH2:21])=[O:30])=[N:18][CH:19]=2)=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: [OH-]
Reactant: Cc1cccnc1Sc1cnc(C#N)c(Oc2cccnc2C)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1cccnc1Sc1cnc(C(N)=O)c(Oc2cccnc2C)c1
Yield: 94.9 %

Procedure:
Concentrated sulfuric acid (8 mL) was added to 5-(3-methylpyridin-2-ylthio)-3-(2-methylpyridin-3-yloxy)picolinonitrile (1.40 g, 4.19 mmol). The reaction was stirred over the weekend, then poured onto ice (100 g), cooled in an ice bath and made basic to pH 10 with 50% NaOH. The reaction mixture was extracted with ethyl acetate, washed with brine, dried (MgSO4), and concentrated to afford 5-(3-methylpyridin-2-ylthio)-3-(2-methylpyridin-3-yloxy)picolinamide (1.40 g, 3.97 mmol, 94.9% yield) as a colorless oil which became a white crystalline solid overnight under vacuo.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]2[CH:9]=[C:10]([C:13]3[CH:14]=[C:15](O)[CH:16]=[CH:17][CH:18]=3)[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1.Cl[CH2:21][C@@H:22]1[CH2:24][O:23]1.C[N:26](C=O)C>O>[CH3:3][N:4]1[C:8]2[CH:9]=[C:10]([C:13]3[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=3)[NH:26][CH2:21][C@H:22]3[CH2:24][O:23]3)[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1
Reactant: Cn1cnc2ccc(-c3cccc(O)c3)cc21
Reactant: ClC[C@@H]1CO1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cn1cnc2ccc(-c3cccc(NC[C@H]4CO4)c3)cc21
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a solution of NaH (161 mg, 6.69 mmol) in DMF (5 mL) was added 3-(1-methyl-1H-benzo[d]imidazol-6-yl)phenol (500 mg, 2.23 mmol) at 27° C. After 0.5 h, (S)-2-(chloromethyl)oxirane (246 mg, 2.68 mmol) was added and the reaction mixture was stirred 16 h, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was used in next step without further purification. (480 mg, yield 77%).
Reaction SMILES: C[C:2]1([CH3:18])[CH2:6][N:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=2[CH3:16])[C:4](=[O:17])N1.[Cl:19][C:20]1[CH:31]=[CH:30][C:23]2[NH:24][C:25]([C@@H:27]([NH2:29])[CH3:28])=[N:26][C:22]=2[CH:21]=1.CN([C:35]([O:39]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Cl:19][C:20]1[CH:31]=[CH:30][C:23]2[NH:24][C:25]([C@@H:27]([NH:29][C:11](=[O:13])[C:10]3[CH:14]=[CH:15][C:7]([N:5]4[CH2:6][CH2:2][CH2:18][CH2:35][O:39][C:4]4=[O:17])=[C:8]([CH3:16])[CH:9]=3)[CH3:28])=[N:26][C:22]=2[CH:21]=1
Reactant: Cc1cc(C(=O)O)ccc1N1CC(C)(C)NC1=O
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)ccc1N1CCCCOC1=O

Procedure:
Prepared analogously to Example 1f from 4-(4,4-dimethyl-2-oxo-imidazolidin-1-yl)-3-methyl-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and DIPEA in THF and purification of the residue by chromatography on silica gel.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:11][C:10](=[S:12])[NH:9][N:8]=2)=[CH:3][CH:2]=1.Br[CH2:14][C:15]#[CH:16].C([O-])(=O)C.[Na+].O>CN(C=O)C>[CH2:16]([S:12][C:10]1[NH:11][C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[N:8][N:9]=1)[C:15]#[CH:14]
Reactant: S=c1[nH]nc(-c2ccncc2)[nH]1
Reactant: C#CCBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCSc1nnc(-c2ccncc2)[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 61.9 %

Procedure:
A mixture of 3-(pyridin-4-yl)-1H-1,2,4-triazole-5(4H)-thione (2 g, 11.2 mmol), 3-bromoprop-1-yne (1.47 g, 12.3 mmol) and sodium acetate (5.34 g, 65.1 mmol) in DMF (20 mL) was stirred for 6 h at room temperature. The reaction mixture was then poured into water (50 mL) and extracted with DCM. The combined organic layers were washed with water three times, dried with Na2SO4, filtered and concentrated to obtain the title compound (1.5 g).