Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=O)[C:7]([F:15])([F:14])[O:6][C:5]2([F:17])[F:16]>C(O)(=O)C.O.[Fe]>[NH2:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([F:17])([F:16])[O:6][C:7]2([F:14])[F:15])=[CH:3][C:2]=1[Cl:1]
Reactant: O=[N+]([O-])c1cc2c(cc1Cl)C(F)(F)OC2(F)F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc2c(cc1Cl)C(F)(F)OC2(F)F
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
To a solution wherein electrolytic iron powder (5.59 g, 100.0 mmol) is in acetic acid (100 ml) and water (10 ml), an acetic acid (20 ml) solution of 5-chloro-6-nitro-1,1,3,3-tetrafluoro-1,3-dihydroisobenzofuran (5.43 g, 20.0 mmol) was added dropwise at 50 to 60° C. over a period of about 10 minutes and further stirred for 30 minutes. The reaction solution was then filtered and water was poured into the filtrate. After the solution was extracted with ethyl acetate, the organic layer was washed with a saturated sodium hydrogencarbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography to give 4.46 g of 6-amino-5-chloro-1,1,3,3-tetrafluoro-1,3-dihydroisobenzofuran.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:7][C:8]1([C:13]([NH:15][C@H:16]2[CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[N:18]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:17]2=[O:35])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1)([OH:6])=[O:5])[CH3:2].C(N(CC)CC)C.[C:43]([O:49][CH2:50]Cl)(=[O:48])[C:44]([CH3:47])([CH3:46])[CH3:45].CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:43]([O:49][CH2:50][CH:7]([P:4]([OH:6])([O:3][CH2:1][CH3:2])=[O:5])[C:8]1([C:13]([NH:15][C@H:16]2[CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[N:18]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:17]2=[O:35])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1)(=[O:48])[C:44]([CH3:47])([CH3:46])[CH3:45]
Reactant: CCOP(=O)(O)CC1(C(=O)N[C@H]2CCc3ccccc3N(CC(=O)OC(C)(C)C)C2=O)CCCC1
Reactant: CC(C)(C)C(=O)OCCl
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(O)C(COC(=O)C(C)(C)C)C1(C(=O)N[C@H]2CCc3ccccc3N(CC(=O)OC(C)(C)C)C2=O)CCCC1

Procedure:
0.6 g of tert-butyl (3S)-3-(1-ethylphosphono-methylcyclopentane-1-carbonylamino)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetate (preparation see Example 17) were reacted with 1.73 ml of triethylamine, 0.86 ml of pivaloyloxymethyl chloride and 0.1 g of dimethylaminopyridine according to the method indicated in Example 6. After chromatography on silica gel (eluent: ethyl acetate), 392 mg of the title compound were obtained as a viscous resin, IR=1740, 1650 cm-1 (CH2Cl2); [α]D20 =-122.90° (c=0.257 in methanol).
Reaction SMILES: [C:1]([C:4]1([CH2:14][S:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)([OH:3])=O.Cl.CN(C)CCCN=C=NCC.Cl.[CH2:33]([O:40][C:41](=[O:45])[C@H:42]([CH3:44])[NH2:43])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(CC)CC)C>O1CCCC1>[C:16]([S:15][CH2:14][C:4]1([C:1]([NH:43][C@H:42]([C:41]([O:40][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:45])[CH3:44])=[O:3])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Reactant: CC(C)(C)SCC1(C(=O)O)CCc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H](NC(=O)C1(CSC(C)(C)C)CCc2ccccc2C1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
Dissolve 2-carboxy-2-(t-butyl)thiomethyl-1,2,3,4-tetrahydronaphthalene (278 mg, 1.0 mmol) in anhydrous tetrahydrofuran (10 mL). Add 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (230 mg, 1.2 mmol), L-alanine benzyl ester hydrochloride (216 mg, 1.00 mmol) and triethylamine (0.132 mL, 1.00 mmol). Stir at room temperature under an argon atmosphere overnight. Partition between ethyl ether and 5% sulfuric acid. Separate the organic phase and wash with water, saturated sodium hydrogen carbonate and brine. Dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography (20% ethyl acetate/hexane) to give the title compound as a clear yellow oil (210 mg, 48%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][C:9]1[N:14]=[C:13]([CH:15]=O)[CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[CH3:15][C:13]1[N:14]=[C:9]([CH2:8][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: Nc1ccccn1
Reactant: Cc1cccc(C=O)n1
Solvent: Cc1ccccc1
Product: Cc1cccc(CNc2ccccn2)n1
Reaction time: 16 h

Procedure:
To a flask were added 1.9 g of 2-aminopyridine, 2.4 g of 6-methyl-2-pyridinecarboxaldehyde and 45 ml toluene. The flask was equipped with a Dean-Stark trap and heated to reflux under nitrogen. After 16 hours, the toluene was removed and 40 ml ethanol were added followed by 0.83 g of sodium borohydride. The mixture was stirred at 22 C under nitrogen for 1 hour, and then 30 ml of water were added slowly. Following removal of the ethanol, 60 ml 1M hydrochloric acid was added cautiously, and the aqueous layer was washed with 20 ml ethyl acetate. After basifying with aqueous ammonium hydroxide, the product was extracted with 50 ml ethyl acetate and the solvent was removed. The product was purified by silica gel chromatography using 74% ethyl acetate, 24% hexane, and 2% methanol resulting in 1.5 g of a yellow oil that solidified on standing.
Reaction SMILES: [NH:1]1[C:9](=[O:10])[C:8]2[NH:7][CH:6]=[N:5][C:4]=2[N:3]=[CH:2]1.S(=O)(=O)(O)O.[F:16][C:17](I)([F:19])[F:18].OO>[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Fe+2].CS(C)=O>[F:16][C:17]([F:19])([F:18])[C:6]1[NH:7][C:8]2[C:9](=[O:10])[NH:1][CH:2]=[N:3][C:4]=2[N:5]=1
Reactant: FC(F)(F)I
Reactant: O=c1[nH]cnc2nc[nH]c12
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: OO
Solvent: CS(C)=O
Product: O=c1[nH]cnc2nc(C(F)(F)F)[nH]c12
Temperature: 65 °C
Reaction time: 0.33 h
Yield: 24 %

Procedure:
0.14 g (1.0 mmol) of hypoxanthine and 0.058 g (0.3 mmol) of ferrocene 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 of dimethyl sulfoxide solution of trifluoromethyl iodide and 0.2 ml of a 30% hydrogen peroxide aqueous solution. The mixture was stirred at 60 to 70° C. for 20 minutes and then the resulting solution was cooled to room temperature. Formation of 8-trifluoromethylhypoxanthine (19F-NMR yield: 24%) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard. 8-Trifluoromethylhypoxanthine was obtained (0.026 g, yield: 13%) by column chromatography.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[C:13]([CH2:23][N:24]([CH3:32])[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[N:15]=[C:9]2[N:8]([CH2:33][C:34]2[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=2[F:41])[CH:7]=1)=[O:5])[CH3:2].O.[CH:43](Cl)(Cl)Cl>CC(O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[C:13]([CH2:23][N:24]([CH3:32])[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=3)[N:15]=[C:9]2[N:8]([CH2:33][C:34]2[C:35]([F:41])=[CH:36][CH:37]=[CH:38][C:39]=2[F:40])[CH:7]=1)=[O:5])([CH3:43])[CH3:2]
Reactant: CCOC(=O)c1cn(Cc2c(F)cccc2F)c2nc(-c3ccc(N)cc3)c(CN(C)Cc3ccccc3)n2c1=O
Reactant: ClC(Cl)Cl
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: O
Solvent: CC(C)O
Product: CC(C)OC(=O)c1cn(Cc2c(F)cccc2F)c2nc(-c3ccc(N)cc3)c(CN(C)Cc3ccccc3)n2c1=O
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 94 %

Procedure:
To a solution of the compound obtained in Example 12 (0.10 g, 0.18 mmol) in chloroform (5 ml) is added a solution of titanium(IV) isopropoxide (0.3 ml, 1.0 mmol) in 2-propanol (10 ml). Then the mixture is refluxed at 80° C. for 8 hours, successively is stirred at room temperature for 150 minutes. To this mixture is added a mixture of chloroform (50 ml) and water (50 ml). The aqueous layer is extracted with chloroform (20 ml). The combined organic extract is dried over Na2SO4 and concentrated under reduced pressure to give the residue, which is chromatographed on silica gel to afford white-brown crystalline solid, which is recrystallized from chloroform-n-hexane to afford pale brown crystals (0.58 g, 94%).
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>>[N:1]1([S:11]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[O:20])=[CH:21][CH:22]=2)(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Reactant: Nc1ccncc1
Product: O=C(Nc1ccncc1)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with 4-aminopyridine (25 mg, 0.26 mmol) using method C. The residue was purified using flash chromatography eluting with 10-50 EtOAc in dichloromethane. The resulting solid was triturated with dichloromethane/hexanes to give 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(pyridin-4-yl)benzamide as a white solid. Yield: 41 mg (40%). 1H-NMR: 10.79 (s, 1H), 8.50-8.47 (m, 2H), 8.06 (d, J=8.5 Hz, 2H), 7.79-7.73 (m, 4H), 7.63 (d, J=8.0 Hz, 1H), 7.23-7.08 (m, 3H) 3.85-3.81 (m, 2H), 2.45 (t, J=7.0, 2H), 1.67-1.59 (m, 2H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH2:40]([N:47]1[CH2:51][CH2:50][N:49]([C@@H:52]([C:56]([CH3:59])([CH3:58])[CH3:57])[C:53](O)=[O:54])[C:48]1=[O:60])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:40]([N:47]1[CH2:51][CH2:50][N:49]([C@@H:52]([C:56]([CH3:58])([CH3:57])[CH3:59])[C:53]([NH:1][C@@H:2]([CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:9][CH:8]=2)=[O:54])[C:48]1=[O:60])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CC(C)(C)[C@@H](C(=O)O)N1CCN(Cc2ccccc2)C1=O
Reactant: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.5 %

Procedure:
A solution containing the product from Example 1H (0.040 g, 0.075 mmol) in THF (0.6 mL) was treated with the product from Example 70A (0.027 g, 0.092 mmol), DEPBT (0.034 g, 0.114 mmol), and N,N-diisopropylethylamine (0.066 mL, 0.379 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane, followed by elution with 0-5% methanol in ethyl acetate to give the title compound (0.045 g, 73% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.80 (s, 9 H), 0.87 (s, 9 H), 1.38 (t, J=11.58 Hz, 1 H), 1.54 (m, 1 H), 2.41 (m, 1 H), 2.64 (m, 3 H), 2.87 (m, 3 H), 3.19 (m, 1 H), 3.53 (m, 4 H), 3.84 (d, J=9.56 Hz, 1 H), 3.95 (m, 1 H), 4.04 (s, 1 H), 4.18 (m, 1 H), 4.29 (m, 2 H), 4.45 (d, J=7.35 Hz, 1 H), 6.88 (d, J=9.56 Hz, 1 H), 7.05 (m, 5 H), 7.30 (m, 8 H), 7.53 (d, J=9.56 Hz, 1 H), 7.90 (m, 5 H), 8.65 (d, J=4.41 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15].[CH2:16](Br)[CH:17]=[CH2:18].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:18][CH:17]=[CH2:16])[C:10]=1[OH:15]
Reactant: Oc1ccccc1Sc1ccccc1Cl
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: C=CCc1cccc(Sc2ccccc2Cl)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
A mixture of 2-(2-chlorophenylthio)phenol (33 g), allyl bromide (25 g) and dried potassium carbonate (29 g) in methyl isobutyl ketone (200 ml) was refluxed under heating for 1.5 hours. After cooling to the ambient temperature, the reaction mixture was filtered, and the filtrate was evaporated under reduced pressure. The resultant oily residue was stirred at 230° C. for 3 hours and then distilled under reduced pressure to give oily 2-(2-chlorophenylthio)-6-allylphenol (32.2 g) bp 157°-162° C./0.7 mmHg.
Reaction SMILES: B.[CH2:2]([N:9]1[C@H:14]([CH3:15])[C:13](=O)[NH:12][C@@H:11]([CH2:17][CH3:18])[C:10]1=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CO.Cl>C1COCC1>[CH2:2]([N:9]1[CH2:10][C@H:11]([CH2:17][CH3:18])[NH:12][CH2:13][C@H:14]1[CH3:15])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC[C@@H]1NC(=O)[C@@H](C)N(Cc2ccccc2)C1=O
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@H]1CN(Cc2ccccc2)[C@H](C)CN1
Temperature: 70 °C
Reaction time: 72 h
Yield: 81.4 %

Procedure:
A solution of borane in THF (1 M, 197 mL) was slowly added to (3S,6R)-1-benzyl-3-ethyl-6-methyl-piperazine-2,5-dione (4.9 g, 19.7 mmol) over 15 min under nitrogen. The reaction mixture was then stirred at 70° C. for 72 h. The resulting solution was cooled to 0° C. and MeOH (60 mL) and 5 M hydrochloric acid (16 mL) were slowly added, then the solution was heated at 70° C. with stirring for 2 h. The solvent was removed in vacuo, and the residue was partitioned between water and Et2O. 1 M aqueous NaOH was added to give pH 12 and the product was extracted with EtOAc (3×). The organic phase was dried (MgSO4), filtered and concentrated to give (2R,5S)-1-benzyl-5-ethyl-2-methyl-piperazine (3.5 g) as a yellow liquid. MS: [M+H]+=219.
Reaction SMILES: [N:1]1([C:5]([C:7]2[N:8]=[CH:9][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C@@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:23]=3)[C:17]([O:19]C)=[O:18])=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].C(O)(=O)C.Cl>O.CN1CCCC1=O>[N:1]1([C:5]([C:7]2[N:8]=[CH:9][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C@@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:23]=3)[C:17]([OH:19])=[O:18])=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CC(=O)O
Product: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(C(=O)O)c1
Temperature: 10 °C
Reaction time: 4 h

Procedure:
To a flask was added methyl 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(1S)-2-methoxy-1-methylethoxy]benzoate (1.0 eq) and N-methylpyrrolidinone (7.6 vols). The contents of the flask were cooled to 10° C. Water (3.9 vols) was added, and the mixture then cooled to approximately −15° C. Sodium hydroxide (1.5 eq) was dissolved in water (2.3 vols), and the sodium hydroxide solution added slowly to the flask over one hour, maintaining the reaction temperature below −10° C. The sodium hydroxide was line washed with water (0.5 vols). The reaction mixture was held for approximately 4 hours. Acetic acid (1.25 eq) was added to the mixture at −10° C. The mixture was allowed to warm to 5° C. Acetic acid (2.37 eq) was added to the mixture, the acetic acid line washed with water (3.5 vols) and the mixture allowed to warm to 22° C. The mixture was seeded, then water (5 vols) was added to the mixture. 2N hydrochloric acid (1.5 eq) was added to the mixture until pH4 was reached. The reaction mixture was stirred for at least 14 hours, then cooled to 10° C., stirred for 1 hour at 10° C. The mixture was filtered. The solid was slurry washed with water (3×2.5 vol). The isolated solid was dried at 25° C. under vacuum to afford the title compound as an off white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([N:10](C2C=CC=CC=2)[C:11](=[O:13])[O-])[N:4]=1.[CH3:20][N:21]([CH3:32])[C:22]1[C:27]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:26][CH:25]=[CH:24][N:23]=1>O1CCOCC1>[CH3:20][N:21]([CH3:32])[C:22]1[C:27]([S:28]([NH:31][C:11]([NH:10][C:5]2[N:4]=[C:3]([O:2][CH3:1])[N:8]=[C:7]([CH3:9])[N:6]=2)=[O:13])(=[O:30])=[O:29])=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: CN(C)c1ncccc1S(N)(=O)=O
Reactant: COc1nc(C)nc(N(C(=O)[O-])c2ccccc2)n1
Solvent: C1COCCO1
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2cccnc2N(C)C)n1
Reaction time: 1 h
Yield: 89.6 %

Procedure:
3.28 g of N-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)phenylcarbamate are added at room temperature to a mixture of 2.41 g of 2-dimethylamino-3-pyridylsulfonamide and 1.9 ml of 1,7-diazabicyclo[5.4.0]undec-7-ene in 30 ml of absolute dioxan. The mixture is stirred for 1 hour at this temperature and then concentrated in vacuo. The residue is stirred in 10 ml of 1N aqueous HCl and filtered. The filter residue is washed with water and ether and dried, affording 3.94 g of the title urea with a melting point of 173°-175° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])([C:11]1[N:12](COC)[CH:13]=[CH:14][N:15]=1)[OH:10].C(O)(=O)C.Cl>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])([C:11]1[NH:15][CH:14]=[CH:13][N:12]=1)[OH:10]
Reactant: COCn1ccnc1C(O)(c1ccc(Cl)cc1Cl)c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: OC(c1ncc[nH]1)(c1ccc(Cl)cc1Cl)c1ccc(Cl)cc1Cl

Procedure:
A solution of 10 g (0.023 mol) of α,α-bis(2,4-dichlorophenyl)-1-(methoxymethyl)imidazole-2-methanol in 150 ml. of glacial acetic acid, 15 ml. of concentrated hydrochloric acid and 15 ml. of water was refluxed for two hours and then concentrated. The residue was dissolved in a small amount of a mixture of ethanol and 2N hydrochloric acid and the solution was extracted with diethyl ether. The extract was dried over sodium sulphate and the ether was distilled off. Diethyl ether and petroleum ether (boiling range 60°-80° C.) were added, the solid substance was filtered off and twice crystallised from isopropyl alcohol with a little ethanol. α,α-Bis(2,4-dichlorophenyl)imidazole-2-methanol was obtained. Melting point 193° C.
Reaction SMILES: Br[C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][CH2:8][O:9][CH2:10][C:4]=2[CH:3]=1.[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[CH:14]=[CH2:15].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].ClCCl>[C:18]([O:17][C:13](=[O:16])[CH:14]=[CH:15][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][CH2:8][O:9][CH2:10][C:4]=2[CH:3]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Brc1cnc2c(c1)COCCN2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CC(C)(C)OC(=O)C=Cc1cnc2c(c1)COCCN2
Temperature: 100 °C

Procedure:
A solution of 3-Bromo-5,7,8,9-tetrahydro-6-oxa-1,9-diaza-benzocycloheptene (0.5 g, 2.2 mmol), tert-butyl acrylate (1.6 mL, 10.9 mmol) and (i-Pr)2EtN (1.1 mL, 6.5 mmol) in propionitrile/DMF (20 mL/5 mL) was de-oxygenated with Ar for 30 min. The mixture was treated with Pd(OAc)2 (49 mg, 0.22 mmol) and P(o-tol)3 (133 mg, 0.44 mmol) then heated to 100° C. for 16 h. The hot mixture was filtered through a pad of celite. The filtrate was diluted with H2O (100 mL) then extracted with dichloromethane (2×75 mL). The combined organic fractions were treated with brine (100 mL), dried over Na2SO4 and concentrated to give a yellow residue. This was subjected to flash chromatography on silica gel using 1.3% methanol:dichloromethane. The appropriate fractions were collected and concentrated to give a cream solid. Yield: 0.4 g (67%); 1H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J=2.1 Hz, 1H), 7.87 (d, J=2.1 Hz, 1H), 7.44 (d, J=16.0 Hz, 1H), 6.87 (br s, 1H), 6.33 (d, J=16.0 Hz, 1H), 4.50 (s, 2H), 3.75-3.72 (m, 2H), 3.22-3.20 (m, 2H), 1.47 (s, 9H); ESI MS m/z 277 [C15H20N2O3+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:20])=[C:5]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)[N:6]=[N:7][CH:8]=1.[H-].[Na+].[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27]Br.O>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][O:2][C:3]1[C:4](=[O:20])[C:5]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)=[N:6][N:7]([CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[C:24]([F:23])([F:33])[F:34])[CH:8]=1
Reactant: COc1cnnc(-c2ccnn2-c2ccccc2)c1O
Reactant: FC(F)(F)c1ccccc1CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cn(Cc2ccccc2C(F)(F)F)nc(-c2ccnn2-c2ccccc2)c1=O
Reaction time: 0.33 h
Yield: 32.4 %

Procedure:
To a solution of 5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4-ol (21 mg) in DMF (0.5 mL) were added tetra n-butylammoniumiodide (9 mg) and 60% NaH oil mixture (4 mg) at 0° C., and the mixture was stirred as it was for 20 min. To the reaction mixture was added 2-(trifluoromethyl)benzyl bromide (24 mg), and the mixture was stirred at room temperature for 60 hr. To the reaction mixture was added water (0.5 mL), and the mixture was extracted with ethyl acetate (2 mL×2) (the extract was separated by an organic layer-separation filter). The extract was distilled by blowing air at 60° C., and the residue was dissolved in DMSO, and purified by preparative HPLC (column: YMC combiprep pro C18 RS, solvent: 10 mM NH4HCO3/MeCN). The obtained eluate containing the title compound was concentrated by blowing air at 60° C. to give the title compound (10.8 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][O:8][C@H:9]2[CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:5][CH:4]=1.[S:16](N)([NH2:19])(=[O:18])=[O:17]>C(COC)OC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C@H:9]2[CH2:13][CH2:12][N:11]([S:16]([NH2:19])(=[O:18])=[O:17])[CH2:10]2)=[CH:14][CH:15]=1
Reactant: COc1ccc(CO[C@H]2CCNC2)cc1
Reactant: NS(N)(=O)=O
Solvent: COCCOC
Product: COc1ccc(CO[C@H]2CCN(S(N)(=O)=O)C2)cc1
Yield: 61.2 %

Procedure:
A mixture of (S)-3-((4-methoxybenzyl)oxy)pyrrolidine (4.50 g, 21.7 mmol) and sulfamide (2.50 g, 26.0 mmol) in dimethoxyethane (100 mL) was refluxed for 72 h. The reaction was concentrated in vacuo. Purification of the residue by column chromatography (30% to 100% gradient ethyl acetate in hexanes) afforded the title compound as a colorless solid (3.80 g, 61%): 1H NMR (300 MHz, DMSO-d6) δ 7.27-7.24 (m, 2H), 6.91-6.88 (m, 2H), 6.74 (s, 2H), 4.39 (s, 2H), 4.16-4.11 (m, 1H), 3.74 (s, 3H), 3.30-3.25 (m, 1H), 3.18-3.10 (m, 3H), 2.00-1.88 (m, 2H); MS (ES+) m/z 287.2 (M+1); MS (ES−) m/z 285.3 (M−1).
Reaction SMILES: [CH:1]1([C:4]2[NH:12][C:7]3=[N:8][CH:9]=[CH:10][CH:11]=[C:6]3[CH:5]=2)[CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:18].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>COCCOC>[CH:1]1([C:4]2[NH:12][C:7]3=[N+:8]([O-:18])[CH:9]=[CH:10][CH:11]=[C:6]3[CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1cnc2[nH]c(C3CC3)cc2c1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: COCCOC
Product: [O-][n+]1cccc2cc(C3CC3)[nH]c21
Temperature: 20 °C
Reaction time: 0.75 h
Yield: 49 %

Procedure:
To a stirred solution of 2-cyclopropyl-1H-pyrrolo[2,3-b]pyridine (7.6 g) in DME (100 ml) was added a solution of m-chloroperoxybenzoic acid (17.9 g) in DME (50 ml), under an atmosphere of nitrogen, keeping the temperature between 20 and 25° C. The resulting suspension was stirred at 20° C. for 45 min and then sodium metabisulphite solution (20 ml, 40%) was added. The mixture was concentrated in vacuo to ˜80 ml. Water (100 ml) was added and the mixture basified by the addition of aqueous potassium carbonate solution. The suspension was stirred for 14 h and then the precipitate was collected by filtration, washed with water and dried to give the title compound (4.1 g).