Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:47]([C:51]1[CH:56]=[CH:55][C:54]([NH2:57])=[CH:53][CH:52]=1)([CH2:49][CH3:50])[CH3:48]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:57][C:54]4[CH:55]=[CH:56][C:51]([CH:47]([CH2:49][CH3:50])[CH3:48])=[CH:52][CH:53]=4)=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(C)c1ccc(N)cc1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)Nc2ccc(C(C)CC)cc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with N-(4-sec-butyl-phenyl)-amine (TCI-US) to give the title compound. LC-MS (ES+) 796 [(M+H)+].
Reaction SMILES: [O:1]=[C:2]1[NH:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[CH:8]=2)[NH:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.C1COCC1>[N:12]1([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2](=[O:1])[NH:11][CH2:10]3)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)CNC(=O)N3)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C1NCc2cc(N3CCNCC3)ccc2N1
Temperature: 25 °C
Reaction time: 6 h
Yield: 134.7 %

Procedure:
To a solution of compound 10 (0.7 g, 2.11 mmol) in a mixture of CH2Cl2 (15 mL) and THF (5 mL) at 0° C. was added TFA (5 mL) and the mixture was stirred at room temperature for 6 h. The solvent was evaporated under vacuum to afford 0.66 g (96%) of compound 6 as a dark brown gum. 1H NMR (500 MHz, DMSO-d6) δ=3.17 (m, 4H, 2CH2), 3.40 (m, 4H, 2CH2), 4.28 (s, 2H, CH2), 6.70 (m, 2H, aromatic-H), 6.73 (m, 1H, aromatic-H), 8.81 (br. s, 1H, NH), 8.86 (br. s, 1H, NH). 13C NMR (125.7 MHz, DMSO-d6) δ=46.11 (CH2), 46.70 (CH2), 48.68 (CH2), 112.21 (aromatic-C), 112.27 (aromatic-C), 117.31 (aromatic-C), 130.28 (aromatic-C), 134.99 (aromatic-C), 143.38 (aromatic-C), 154.82 (C═O). Calculated (%) for C14H16F3N4O2 (329.12); C, 51.06; H, 4.90; N, 17.01. found (%); C, 51.01; H, 4.95; N, 16.95.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][NH:8][C:7](=[O:12])[C:6]=2[CH:13]=1.[H-].[Na+].Cl.Cl[CH2:18][C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([CH2:18][C:19]3[N:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[C:7](=[O:12])[C:6]=2[CH:13]=1
Reactant: O=C1NCCOc2ccc(Br)cc21
Reactant: ClCc1ncccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2cc(Br)ccc2OCCN1Cc1ncccn1
Temperature: 25 °C

Procedure:
7-Bromo-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (1.0 g, 4.13 mmol) was dissolved in DMF (10 ml) cooled down in a ice/water bath and treated with sodium hydride (60% dispersion) (363 mg, 9.08 mmol) portion wise. After 10 min a solution of 2-(chloromethyl)pyrimidine hydrochloride (813 mg, 4.96 mmol) in DMF (4 ml) was added, the reaction mixture warmed up to room temperature and quenched with 12 mL of water after it was complete. The reaction mixture was extracted with EtOAc and water and the organic phase was dried, evaporated and purified by silica gel chromatography (95% DCM/MeOH) to afford 7-bromo-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:18][CH2:19][CH2:20][NH2:21])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.Br[CH2:23][CH2:24][O:25][C:26]1[CH:33]=[C:32]([N+:34]([O-:36])=[O:35])[CH:31]=[CH:30][C:27]=1[C:28]#[N:29]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:18][CH2:19][CH2:20][NH:21][CH2:23][CH2:24][O:25][C:26]2[CH:33]=[C:32]([N+:34]([O-:36])=[O:35])[CH:31]=[CH:30][C:27]=2[C:28]#[N:29])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1OCCBr
Reactant: NCCNc1nc(Cl)nc2c1CCC2c1ccc(F)cc1
Solvent: CN(C)C=O
Product: N#Cc1ccc([N+](=O)[O-])cc1OCCNCCNc1nc(Cl)nc2c1CCC2c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.7 %

Procedure:
To a solution of N1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)ethane-1,2-diamine {Preparation Sc Step (1), 1.0 g, 3.265 mmol} in DMF (5 mL) was added TEA (0.495 g, 4.89 mmol) followed by 2-(2-bromoethoxy)-4-nitrobenzonitrile (Preparation N, 1.05 g, 3.91 mmol) at room temperature. The reaction mixture was stirred at rt for 18 h. The solvent was removed under reduced pressure and the residue was taken in dichloromethane (5 mL) and silica (1 g). The resultant slurry of the compound in silica was subjected to flash chromatography using a Teledyne Isco instrument (12 g RediSep silica column, 10% methanol in chloroform) to get 2-(2-(2-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ylamino)ethylamino)ethoxy)-4-nitrobenzonitrile (0.35 g, 21.7%) as a light yellow solid. LC-MS (M+H)+=497.2. 1H NMR (400 MHz, CDCl3) δ ppm 7.93-7.91 (1H, d, J=6.8 Hz), 7.90 (1H, s), 7.86-7.85 (1H, m), 7.12-7.00 (2H, m), 6.98-6.96 (2H, m), 5.30 (1H, br s), 4.34-4.32 (2H, m), 4.26-4.24 (1H, m), 3.70-3.66 (2H, m), 3.21-3.19 (2H, m), 3.04-3.02 (2H, m), 2.78-2.63 (3H, m), 1.99-1.98 (1H, m).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[CH:13])[CH:10]=2)[O:5][CH2:4][CH2:3]1.C([Li])CCC.Br[C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=1>O1CCCC1.CCCCCC>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCO3)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Reaction vessels used in this procedure were flame dried under vacuum and all operations were carried out in an oxygen-free, argon or nitrogen atmosphere. To a solution of 509.4 mg (2.74 mmol) of 4,4-dimethyl-6-ethynyl chroman (from Example 10) in 4 ml of dry tetrahydrofuran at 0° C. was added dropwise 1.72 ml of 1.6M (2.75 mmol) of n-butyl lithium in hexane. Stirring was commenced at 0° C. for 30 minutes and at room temperature for 15 minutes, after which the solution was cooled again to 0° C. and then treated with a solution of 380 mg (2.79 mmol) of fused zinc chloride in 5 ml of dry tetrahydrofuran using a double ended needle. The resulting solution was stirred at 0° C. for 1 hour and then at room temperature for 15 minutes. A solution of 628.6 mg (2.74 mmol) of ethyl 4-bromobenzoate in 4 ml of dry tetrahydrofuran was transferred by double ended needle into a suspension of 380 mg (0.33 mmol) of tetrakistriphenylphosphine palladium in 5 ml dry tetrahydrofuran and stirred at room temperature for 15 minutes, then treated by double ended needle with the solution of alkynyl zinc chloride prepared above. The mixture was stirred at room temperature for 20 hours and then quenched with ice and 30 ml of 3N hydrogen chloride. The mixture was then extracted with 3×75 ml ether and ether extracts were combined and washed successively with saturated NaHCO3 and saturated NaCl solutions and then dried (MgSO4). Solvent was removed in vacuo and the residue further purified by flash chromatography (silica; 10% ethyl acetate in hexane) to obtain the captioned compound as a white solid. PMR (CDCl3): δ 1.36 (6H), 1.42 (3H, t, J~7.3 Hz), 1.82-1.86 (2H, m), 4.21-4.25 (2H, m), 4.40 (2H, q, J~7.3 Hz), 6.79 (1H, d, J~8.1 Hz), 7.28 (1H, dd, J~8.1 Hz, 2.2 Hz), 7.50 (1H, d, J~2.2 Hz), 7.58 (2H, d, J~8.7 Hz), 8.03 (2H, d, J~8.7 Hz).
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[N:19]=[N:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-:28].Cl>C1COCC1.O.O>[C:24]([C:21]1[N:20]=[N:19][C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:3])=[O:26])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)=[CH:23][CH:22]=1)(=[O:28])[NH2:25].[C:24]([C:21]1[N:20]=[N:19][C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:26])=[O:3])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)=[CH:23][CH:22]=1)#[N:25]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ccc(C#N)nn3)cc(C)c21
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccc(C#N)nn2)cc2c1C(CC(=O)O)OB2O
Product: Cc1cc(Oc2ccc(C(N)=O)nn2)cc2c1C(CC(=O)O)OB2O
Temperature: 0 °C
Reaction time: 20 h
Yield: 11 %
Yield: 26 %

Procedure:
To a solution of [6-(6-cyano-pyridazin-3-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.25 g, 0.7 mmol) in THF:H2O (1:1, 6 mL) at 0° C. was added a solution of LiOH (0.025 g, 1.06 ml) in water (1 mL). The solution was stirred at 0° C. for 20 hours then acidified to pH 3 with 1N HCl and extracted with EtOAc (2×10 mL). The organic extracts were dried and concentrated in vacuo. The residue was purified by preparative HPLC to give [6-(6-carbamoyl-pyridazin-3-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid (0.025 g, 11%) and [6-(6-cyano-pyridazin-3-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid (0.058 g, 26%).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:12][S:13](Cl)(=[O:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:24]=[C:25]1[CH2:30][NH:29][CH2:28][CH2:27][NH:26]1>ClCCl.N1C=CC=CC=1>[CH2:17]([CH:11]([CH2:12][S:13]([N:29]1[CH2:28][CH2:27][NH:26][C:25](=[O:24])[CH2:30]1)(=[O:15])=[O:14])[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(OCc1ccccc1)C(Cc1ccccc1)CS(=O)(=O)Cl
Reactant: O=C1CNCCN1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1CN(S(=O)(=O)CC(Cc2ccccc2)C(=O)OCc2ccccc2)CCN1
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
To the resultant compound from Example 11C (320.5 mg, 0.908 mmol) in dichloromethane (5 mL) at -10° C. was added 2-oxopiperazine (140 mg, 1.40 mmol, Yu et al. J. Med. Chem. 1900, 31, 1435) in pyridine (2 mL). After 30 min at -10° C. and 30 min at ambient temperature, the solvent was evaporated and the residue was partitioned between ether and 0.5 M H3PO4. The organic layer was washed with 0.5 M H3PO4, saturated NaHCO3 solution and brine, and then was dried over MgSO4 and evaporated. Chromatography of the residue on silica gel with 2% methanol in chloroform afforded 237.1 mg (63%) of the desired product as a foam: TLC (5% methanol/95% chloroform) Rf =0.26; 1H NMR (CDCl3) 7.43-7.07 (m, 10H), 5.97 (br, 1H), 5.12 (d, 1H), 5.08 (d, 1H), 3.82 (d, 1H), 3.78 (d, 1H), 3.55 (dd, 1H), 3.43-3.17 (m, 5H), 3.07 (dd, 1H), 3.01 (dd, 1H), 2.87 (dd, 1H).
Reaction SMILES: [C:1](Cl)(=[O:9])[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N[C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[NH:14][N:13]=1.[N:25]1C=CC=CC=1>>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[NH:14][N:13]=[C:12]([C:1]([O:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[O:9])[C:16]=2[NH2:25])=[CH:18][CH:19]=1
Reactant: c1ccncc1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1ccc(-c2cc(N)n[nH]2)cc1
Product: COc1ccc(-c2[nH]nc(C(=O)Oc3ccccc3)c2N)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Phenyl chlorocarbonate (0.87 ml) was added to a solution of 3-amino-5-(4-methoxyphenyl)pyrazole (1.19 g) in pyridine (10 ml), and the mixture was stirred at room temperature for 6 hours. The reaction solution was partitioned between ethyl acetate (50 ml) and water (30 ml), and the organic layer was washed with 1 N hydrochloric acid (50 ml×2), saturated aqueous sodium bicarbonate (50 ml) and saturated brine (50 ml) and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled away. The resulting residue was crystallized from ethyl acetate/hexane to obtain the title compound (0.95 g) as pale yellow crystals (melting point: 286-291° C.).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[O:15][C:16]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:17][C:18](=[O:20])[CH:19]=2)[CH:9]=1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH2:7][C:8]1[CH:9]=[C:10]([C:14]2[O:15][C:16]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:17][C:18](=[O:20])[CH:19]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2cc(=O)cc(N3CCOCC3)o2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(-c2cc(=O)cc(N3CCOCC3)o2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
[3-(6-Morpholine-4-yl-4-oxo-4H-pyran-2yl)-phenyl]carbamic acid tert-butyl ester (3.4 g, 9.2 mmol) was dissolved in 25% trifluoroacetic acid in dichloromethane mixture (30 ml) and stirred for 1 hour at room temperature. The reaction was concentrated in vacuo, precipitated with saturated NaHCO3, filtered, washed with diethyl ether and dried to yield (3-amino-phenyl)-6-morpholin-4-yl-pyran-4-one as a white solid (2.1 g, 85%). m/z (LC-MS, ESP): 273 (M++1).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:7])=[N:5][N:6]=1.[CH2:8]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].Cl>N1C=CC=CC=1>[CH2:8]([C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH:1][C:2]2[S:3][C:4]([CH3:7])=[N:5][N:6]=2)(=[O:28])=[O:27])=[CH:24][CH:25]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: Cc1nnc(N)s1
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nnc(C)s2)cc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
2-Amino-5-methyl-1,3,4-thiadiazole (150 mg, 1.3 mmol) was suspended in pyridine (0.5 mL). p-Dodecylbenzenesulfonyl chloride (300 mg, 0.87 mmol) was added slowly at 0° C. The reaction mixture was then heated to 95° C. and was stirred at this temperature for 1 h. The reaction mixture was then added to aqueous 10% HCl (5 mL) and the resulting mixture extracted with ethyl acetate (3×10 mL). The organic extracts were washed with water, brine, dried over anhydrous Na2SO4, filtered, and volatiles evaporated to yield a solid mass. Chromatography on silica gel (70-230 mesh) eluted with 2% MeOH in CH2Cl2 gave the product (310 mg, 0.73 mmol, 84%). Recrystallization from hexanes:ethyl acetate (3:7) gave an analytical sample, mp 149-150° C.; 1H NMR (500 MHz, CDCl3) δ 0.88 (3, t, J=7.0 Hz), 1.20-1.36 (18, m), 1.54-1.63 (2, m), 2.51 (3, s), 2.63 (2, t, J=7.5 Hz), 7.25 (2, d, J=7.5 Hz), 7.83 (2, d, J=7.5 Hz), 12.36 (1, br s); 13C NMR (125 MHz, CDCl3) δ 14.1, 16.5, 22.7, 29.2, 29.3, 29.4, 29.5, 29.6, 31.1, 31.9, 35.9, 126.4, 128.8, 138.3, 148.3, 154.1, 168.6; MS (ESI+, m/z) Calcd for C21H34N3O2S2 424.2092. found 424.20 (M+H)+; HRMS (ESI+, m/z) Calcd for C21H34N3O2S2 424.2092. found 424.2085 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([N:12]2C(=O)C3C(=CC=CC=3)C2=O)[C:7]([Cl:11])=[C:8]([Cl:10])[CH:9]=1)=[O:4].O.NN>C(O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([NH2:12])[C:7]([Cl:11])=[C:8]([Cl:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(Cl)c(Cl)n1N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: COC(=O)c1cc(Cl)c(Cl)n1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
A mixture of 4,5-dichloro-1-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-1H-pyrrole-2-carboxylic acid methyl ester (5.44 g) and hydrazine monohydrate (1.57 mL) in ethanol was stirred at rt overnight, by which time TLC showed complete conversion; then the solids were filtered off, the filtrate was concentrated and worked up with EtOAc and water; EtOAc phase was washed with sat. NaCl solution and dried over anhydrous sodium sulfate, filtered, concentrated, the crude was column purified (EtOAc/Hexanes) to give desired product (2.21 g). ESI (m/z): 209 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[CH:11]=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.[Li]CCCC.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1COCC1.CCCCCC>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C:9]1[N:10]=[C:11]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:12]([CH3:13])[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: Cn1cnc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)n1C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 1.1 g (3.25 mmol) of 5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)-1-methyl-imidazole in 30 mL of dry THF was cooled in a −78° C. bath and 1.7 mL of 2.5 M n-BuLi in hexane was dropwise added. After stirring the solution for 1 h it was added with a canula to 0.623 mL of ethyl chloroformate in THF cooled in a −78° C. bath. The cold bath was removed and the reaction was stirred for 1 h then quenched with water. The mixture was extracted with EtOAc. The EtOAc layer was washed with brine, dried and concentrated. The residue was chromatographed using a gradient of 10-20% EtOAc-hexane to isolate the desired product.
Reaction SMILES: [I:1]Cl.[F:3][S:4]([OH:7])(=[O:6])=[O:5].[F:8][C:9]([F:16])([F:15])[C:10]([F:14])=[C:11]([F:13])[F:12]>>[S:4]([F:3])([O:7][C:11]([F:13])([F:12])[C:10]([F:14])([I:1])[C:9]([F:16])([F:15])[F:8])(=[O:6])=[O:5]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: ClI
Reactant: O=S(=O)(O)F
Product: O=S(=O)(F)OC(F)(F)C(F)(I)C(F)(F)F
Temperature: 0 °C
Reaction time: 4 h
Yield: 39.9 %

Procedure:
Into a 1.3-liter stainless steel tube was charged a mixture of iodine monochloride (130 g, 0.80 mol) and fluorosulfonic acid (88 g, 0.88 mol). The tube was sealed and cooled, then hexafluoropropylene (144 g, 0.96 mol) was transferred into the tube. The reaction mixture was kept at 25° C. for 2 hr, 50° C. for 2 hr and 80° C. for 4 hr. The product was unloaded from the shaker tube and poured into ice water. The bottom organic layer was separated, washed with water and distilled to afford the title product (120 g, 40% yield) as a clear liquid, bp. 47° C./6.7 kPa. 19F NMR (188.24 MHz, CDCl3): -74.5 (m, 3F), -77.0 (m, AB-pattern, 2F), -148.2 (m, 1F), +49.7 (m, 1F).
Reaction SMILES: CCCCCC.[Na].[C:8]([CH2:10][C:11]1[C:12]([C:17]#[N:18])=[N:13][CH:14]=[CH:15][CH:16]=1)#[N:9].[CH3:19][OH:20]>>[CH3:19][O:20][C:8]1[CH:10]=[C:11]2[C:12](=[C:17]([NH2:18])[N:9]=1)[N:13]=[CH:14][CH:15]=[CH:16]2
Reactant: N#CCc1cccnc1C#N
Reactant: CO
Agent: [Na]
Solvent: CCCCCC
Product: COc1cc2cccnc2c(N)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 9 %

Procedure:
To an oven-dried 250 mL flask under a nitrogen atmosphere was added anhydrous MeOH (200 mL). Na metal (1.07 g, 44 mmol) was weighed to a small beaker containing hexane and then transferred to the reaction vessel. After dissolution of the sodium, 3-cyanomethyl-pyridine-2-carbonitrile (5.3 g, 37 mmol) dissolved in anhydrous MeOH (10 mL) was added to the reaction. The resulting solution was heated at 80° C. for 3 hours, then stirred at room temperature overnight. The reaction mixture was concentrated to remove MeOH and extracted into CH2Cl2 (2×200 mL). The organic phases were combined, dried over Na2SO4, filtered, concentrated and unsuccessfully chromatographed (2% MeOH/CH2Cl2). The mixed fractions were combined and recrystalized from EtOAc/hexane affording 1.16 g (18%) of the title compound as a yellow solid. The mother liquor was rechromatographed (50% EtOAc/hexanes) to afford an additional 560 mg (9%) of product: mp decomposes above 110° C.; MS (+) APCI m/z 176 [M+H]+.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:7][C:6]=2[CH:14]=1.[ClH:15].N([O-])=O.[Na+].[S:20](=[O:22])=[O:21]>C(O)(=O)C.[Cu](Cl)Cl.C1C=CC=CC=1.O>[CH:4]1[C:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:7][C:6]=2[CH:14]=[C:2]([S:20]([Cl:15])(=[O:22])=[O:21])[CH:3]=1
Reactant: O=S=O
Reactant: Cl
Reactant: Nc1ccc2c(c1)oc1ccccc12
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: O=S(=O)(Cl)c1ccc2c(c1)oc1ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Aminodibenzofuran (10 g, 54.6 mol) was diazotized by dissolving in 180 mL glacial acetic acid, 50 mL water, and 14 mL concentrated hydrochloric acid at 0° C. and adding 15 mL of a 5.5 M aqueous solution of sodium nitrite. The resulting mixture was stirred for 1 hour before pouring into a solution of copper(II)chloride (2.0 g, 14.9 mmol) in 240 mL of a 1:1 mixture of benzene and glacial acetic acid saturated with sulfur dioxide. This mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction was partitioned between water and chloroform. The chloroform layer was washed with water, dried over magnesium sulfate, filtered, and concentrated to give the title compound as a yellowish solid; melting point=142-144° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21](=[O:22])[CH2:20][C:15]2([CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:14][C:13]1=[O:23].[Cl:24][C:25]1[C:30]([C:31]#[N:32])=[CH:29][CH:28]=[CH:27][N:26]=1.C(N(CC)CC)C>C(O)C>[O:23]=[C:13]1[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][N:3]2[CH2:4][CH2:5][N:6]([C:25]3[C:30]([C:31]#[N:32])=[CH:29][CH:28]=[CH:27][N:26]=3)[CH2:7][CH:2]2[CH3:1])[C:21](=[O:22])[CH2:20][C:15]2([CH2:16][CH2:17][CH2:18][CH2:19]2)[CH2:14]1.[ClH:24]
Reactant: N#Cc1cccnc1Cl
Reactant: CC1CNCCN1CCCCN1C(=O)CC2(CCCC2)CC1=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC1CN(c2ncccc2C#N)CCN1CCCCN1C(=O)CC2(CCCC2)CC1=O
Product: Cl

Procedure:
The product of Procedure 4, 3.38 g. (0.0105 mole) was caused to react with 1.46 g. (0.0105 mole) of 2-chloro-3-cyanopyridine in the presence of 1.06 g. (0.0105 mole) of triethylamine in 40 ml. of ethanol in a pressure vessel as described in Procedure 2. The crude product, 3.58 g., was recovered as an oil which was dissolved in 30 ml. of ethanol and treated with 2 molecular proportions of ethanolic hydrogen chloride. The solvent was removed by distillation, and the residue was dried by azeotropic distillation with benzene which resulted in crystallization of the desired product as the monohydrochloride, m.p. 181°-183°.