Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.Cl[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][N:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO.[Pd]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([O:11][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([NH2:1])[CH:10]=2)=[N:14][CH:15]=1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1ccc(Oc2ccc(N)c(N)c2)nc1

Procedure:
2-Nitro-4-hydroxyaniline was reacted with 2-chloro-5-nitropyridine and K2CO3 in DMF at rt, followed by hydrogenation over Pd/C in MeOH, afforded the title compound; MS m/e 217 (M+1).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1([C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5]1.O.OC1C2N=NNC=2C=CC=1.[C:29]([O:33][C:34](NC1(C(O)=O)CCCC1)=[O:35])([CH3:32])([CH3:31])[CH3:30].CN1CCNCC1>CN(C=O)C>[CH3:17][N:14]1[CH2:15][CH2:16][N:11]([C:9]([C:4]2([NH:3][C:34](=[O:35])[O:33][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:8][CH2:7][CH2:6][CH2:5]2)=[O:10])[CH2:12][CH2:13]1
Reactant: CN1CCN(C(=O)C2(N)CCCC2)CC1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCCC1
Agent: CN1CCNCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(C(=O)C2(NC(=O)OC(C)(C)C)CCCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
(1-Aminocyclopentyl)(4-methyl-1-piperazinyl)methanone dihydrochloride ##STR204## 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.49 g, 13.0 mmol) was added portionwise to a cooled (4° C.) solution of hydroxybenzotriazole hydrate (1.49 g, 11.0 mmol) and 1-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylic acid (2.29 g, 10.0 mmol) in DMF (15 ml), and the mixture stirred for 30 min. N-Methylpiperazine (1.10 g, 11.0 mmol) was added, the reaction stirred for 30 min. allowed to warm to room temperature and stirring continued for a further 17 h. The reaction mixture was evaporated in vacuo, and the residual yellow oil partitioned between saturated Na2CO3 solution and EtOAc. The layers were separated, the aqueous phase extracted with EtOAc, and the combined organic solutions dried (MgSO4) and concentrated in vacuo. The residual solid was pre-adsorbed onto silica gel and purified by column chromatography upon silica gel using an elution gradient of CH2Cl2 -MeOH-0.880 NH3 (97.5:2.5:0.25 to 90:10:1) and triturated with Et2O to afford tert-butyl 1-[(4-methyl-1-piperazinyl)carbonyl]cyclopentylcarbamate (2.31 g, 7.4 mmol) as a crystalline solid.
Reaction SMILES: C([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17](O)=O)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[NH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>ClCCl>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[CH2:23]([N:21]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:20])[S:12][CH:13]=1)[CH2:22][CH2:27][CH2:26][CH2:25][CH2:29][CH3:30]
Reactant: Nc1cccnc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)O)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1cccnc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A compound obtained using {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}acetic acid synthesized in Example 3 and 3-aminopyridine as starting materials and by an operation similar to that of Example 293-1 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction solution was concentrated under reduced pressure, azeotroped with diethyl ether, and the precipitated solid was collected by filtration to give the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([O:35][CH2:36][CH2:37][N:38]3[C:42]4=[CH:43][CH:44]=[CH:45][CH2:46][CH:41]4[NH:40][CH2:39]3)=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([O:35][CH2:36][CH2:37][N:38]3[C:42]4=[CH:43][CH:44]=[CH:45][CH2:46][CH:41]4[NH:40][CH2:39]3)=[CH:31][CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)ccc(OCCN3CNC4CC=CC=C43)c2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2c(C)ccc(OCCN3CNC4CC=CC=C43)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-butyl-7-[2-(tetrahydrobenzimidazol-1-yl)-ethoxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [C:1]([O:6][CH:7]([CH2:14][CH3:15])[C:8]([C:11]([OH:13])=[O:12])([F:10])[F:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].C1[CH2:20][O:19][CH2:18]C1.COCCl>O>[C:1]([O:6][CH:7]([CH2:14][CH3:15])[C:8]([C:11]([O:13][CH2:18][O:19][CH3:20])=[O:12])([F:10])[F:9])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C1CCOC1
Reactant: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)O
Agent: COCCl
Solvent: O
Product: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)OCOC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
Under nitrogen, a 20 mL reactor was charged with 70 mg (0.25 mmol) of 1-hydroxycarbonyl-1,1-difluoro-2-butyl methacrylate (purity: 78%) and 3 mL of THF (dehydrated one), followed by cooling to 0° C. Then, 65 μL (0.47 mmol, 1.9 eq) was added, followed by stirring at 0° C. for 10 min. Then, 30 μL (0.40 mmol, 1.6 eq) of chloromethyl methyl ether was added, followed by stirring at 0° C. for 20 min. Then, 5 mL of water was added to the reaction solution, followed by extraction with diisopropyl ether two times and removal of water with magnesium sulfate. After conducting filtration, diisopropyl ether was distilled off, thereby obtaining 58 mg of the target 1-(methoxymethyl)oxycarbonyl-1,1-difluoro-2-butyl methacrylate. Upon this, purity was 96%, and yield was 83%.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.CO[CH:17]1[CH2:21][CH2:20][CH:19](OC)O1.CO>C1(C)C=CC=CC=1.C(O)(=O)C>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=2)[CH:17]=[CH:21][CH:20]=[CH:19]1
Reactant: COC1CCC(OC)O1
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C=Cc1ccc(-n2cccc2)cc1

Procedure:
A solution of ethyl 4-aminocinnamate (1 g) and 2,5-dimethoxytetrahydrofuran (0.677 ml) in toluene (3 ml) and acetic acid (3 ml) was refluxed for 5 hours with removing methanol. After cooling, the mixture was washed with water twice and saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo. The residue was purified with column chromatography eluting with n-hexane -ethyl acetate to give ethyl 4-(1-pyrrolyl)cinnamate (740 mg) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.CN(C)C=O.[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26][NH2:27]>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:27][CH2:26][CH2:25][CH2:24][N:23]([CH3:28])[CH3:22]
Reactant: CN(C)CCCN
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN(C)CCCN/C=C1\C(=O)NC(=O)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
A mixture of 6-bromo-4-(methoxymethylene)-isoquinoline-1,3(2H,4H)-dione (70.5 mg, 0.25 mmole), dimethylformamide (2 mL) and N1,N1-dimethylpropane-1,3-diamine (25.6 mg, 0.25 mmole) is stirred at room temperature for one hour. The reaction mixture is diluted with ether, filtered and washed with fresh ether and dried to give a light brown solid, 65.8 mg, (66% yield) MS (ES+): 352.2, (M+H).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[C:8]([NH:9][CH2:10][CH2:11][O:12][CH3:13])=[N:7][O:6][N:5]=1.[F:15][C:16]([F:26])([F:25])[C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[F:24])[NH2:20]>>[F:24][C:23]1[CH:22]=[CH:21][C:19]([NH:20][C:3]([C:4]2[C:8]([NH:9][CH2:10][CH2:11][O:12][CH3:13])=[N:7][O:6][N:5]=2)=[N:2][OH:1])=[CH:18][C:17]=1[C:16]([F:15])([F:25])[F:26]
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: COCCNc1nonc1C(Cl)=NO
Product: COCCNc1nonc1C(=NO)Nc1ccc(F)c(C(F)(F)F)c1

Procedure:
The desired compound was prepared according to the procedure of Example 13, step A, using N-hydroxy-4-[(2-methoxyethyl)amino]-1,2,5-oxadiazole-3-carboximidoyl chloride [made according to Example 1, steps A through E] and 3-trifluoromethyl-4-fluoroaniline [Aldrich, product #217778] as the starting materials in quantitative yield. LCMS for C13H14F4N5O3 (M+H)+: m/z=364.0. 1H NMR (400 MHz, CD3OD): δ 7.15 (m, 2 H), 7.08 (m, 1 H), 3.60 (t, J=5.3 Hz, 2 H), 3.46 (t, J=5.3 Hz, 2 H), 3.38 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][CH2:13][N:12]3[C:7](=[C:8]([C:22]([OH:24])=O)[CH:9]=[C:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:11]3=[O:15])[C:6]=2[CH:25]=1.C(Cl)(=O)C(Cl)=O.[CH3:32][N:33]([CH3:36])C=O.[C:37]([O:40][CH2:41][CH3:42])(=O)[CH3:38]>C(Cl)Cl.COC(C)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][CH2:13][N:12]3[C:7](=[C:8]([C:22]([N:33]4[CH2:32][CH2:38][C@H:37]([O:40][CH2:41][CH3:42])[CH2:36]4)=[O:24])[CH:9]=[C:10]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:11]3=[O:15])[C:6]=2[CH:25]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(-c2ccccc2)c(=O)n2c1-c1cc(Cl)ccc1CC2
Reactant: CCOC(C)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: CCO[C@H]1CCN(C(=O)c2cc(-c3ccccc3)c(=O)n3c2-c2cc(Cl)ccc2CC3)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
7.04 g of 10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-benzo[a]quinolizine-1-carboxylic acid are suspended in 100 ml of ethyl acetate under argon and treated with 2.1 ml of oxalyl chloride. Subsequently, 0.2 ml of N,N-dimethylformamide is added, whereby an evolution of gas is observed. The mixture is left to stir at room temperature for 30 minutes, a further 0.2 ml of oxalyl chloride and thereupon 0.1 ml of N,N-dimethylformamide are added thereto and the mixture is left to stir at room temperature for a further 30 minutes. The reaction mixture is cooled to 0°-5° C. in an ice bath, whereby crystals separate. 13.3 ml of triethylamine are added and a solution of 2.53 g of (S)-3-ethoxypyrrolidine in 25 ml of ethyl acetate is subsequently added dropwise. The mixture is subsequently stirred at about 0° C. for 30 minutes, washed twice with 50 ml of water each time and the combined aqueous phases are extracted once with 20 ml of ethyl acetate. The combined organic phases are dried over sodium sulphate, filtered and evaporated, whereby 9.0 g of crude product are obtained. The crude product is dissolved in 50 ml of methylene chloride and filtered through 45 g of silica gel (methylene chloride/acetone 9:1), whereby 8.6 g of yellow crystals are obtained. These are taken up in 100 ml of tert.-butyl methyl ether and heated to reflux for 1 hour. The mixture is left to cool to room temperature and the crystals (6.95 g) are filtered off under suction. 5.5 g the thus-obtained crude product are recrystallized from 55 ml of ethyl acetate, whereby, for crystallization, the mixture is cooled in an ice bath. After drying at 80° C./0.05 mm (18 hrs.) there are obtained 4.2 g of (S)-1-[(10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-benzo[a]quinolizin-1-yl)carbonyl]-3-ethoxypyrrolidine of m.p. 134°-136° C.
Reaction SMILES: S(C1C=CC=CC=1)C1C=CC=CC=1.[C:14]1([C:19]2[CH:20]=[C:21]([CH:40]=[CH:41][C:42]=2[O:43][C:44]([F:47])([F:46])[F:45])[CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C@@H:30]([C:35]3[CH:39]=[CH:38][O:37][N:36]=3)[CH2:31][C:32]([OH:34])=[O:33])=[CH:26][CH:25]=2)[CH2:18][CH2:17][CH2:16][CH:15]=1>CO.[Pd]>[CH:14]1([C:19]2[CH:20]=[C:21]([CH:40]=[CH:41][C:42]=2[O:43][C:44]([F:46])([F:47])[F:45])[CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C@@H:30]([C:35]3[CH:39]=[CH:38][O:37][N:36]=3)[CH2:31][C:32]([OH:34])=[O:33])=[CH:26][CH:25]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C(O)C[C@@H](c1ccc(OCc2ccc(OC(F)(F)F)c(C3=CCCC3)c2)cc1)c1ccon1
Agent: [Pd]
Agent: c1ccc(Sc2ccccc2)cc1
Solvent: CO
Product: O=C(O)C[C@@H](c1ccc(OCc2ccc(OC(F)(F)F)c(C3CCCC3)c2)cc1)c1ccon1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of Pd/C (20.0 mg, 10%) with Ph2S (1.0%) in MeOH (5.0 mL), was added 20 (25.0 mg, 0.164 mmol) in MeOH (1.0 mL). The reaction mixture was purged with hydrogen three times. The mixture was then stirred under hydrogen at room temperature overnight. The catalyst was filtered off, and the solvent was evaporated to give the title compound 23. 1H NMR (CD3CN) δ 1.55-2.02 (m, 8H), 2.93 (dd, J=7.3, 16.4 Hz, 1 H), 3.16 (dd, J=7.3, 16.4 Hz, 1 H), 3.33 (m, 1 H), 4.53 (m, 1 H), 5.05 (s, 2 H), 6.24 (d, J=1.7 Hz, 1H), 6.94 (d, J=6.6 Hz, 2H), 7.22-7.26 (m, 4H), 7.49 (d, J=5.0 Hz, 1H), 8.45 (d, J=1.7 Hz, 1H). MS ESI (pos.) m/e: 476 (M+H).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li][CH2:15]CCC.IC.OC1O[C@@H](CO)[C@H](O)[C@H](O)[C@H]1O>>[CH3:15][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: [Li]CCCC
Agent: OC[C@@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O
Solvent: CI
Product: CC1c2ccccc2-c2ccccc21

Procedure:
Fluorene (15.0 g, 90.4 mmol), n-BuLi (48.1 ml, 120 mmol, 2.5 M in hexane), RX=iodomethane (19.3 g, 136 mmol). 40 was isolated as a yellowish waxy solid (16.2 g, quant.). The analytical data were identical to those in the literature (M. A. Schmidt, H. G. Alt, W. Milius, J. Organomet. Chem. 1996, 525, 15).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].CN(C)C1C=CC=CC=1.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1(C)C=CC=CC=1>[CH2:25]([O:24][C:22]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:23])[CH3:26]
Reactant: CCOC(=O)CCCCCO
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)CCCCCOC(=O)OCC
Temperature: 0 °C
Yield: 48.3 %

Procedure:
160 g of ethyl 6-hydroxy-hexanoate, 145.4 g of N,N-dimethylaniline and 200 ml of anhydrous toluene are placed in a round flask which is provided with a dropping funnel, a thermometer and a stirrer. 119.4 g of ethyl chloroformate are added dropwise at 25° C. within a half hour while stirring. The reaction mixture is held under reflux for 3 hours. After cooling the reaction mixture is poured on to ice-water, the organic phase is washed twice with water, with 100 ml of a 5% hydrochloric acid solution and then neutral with water. After drying over sodium sulphate the solvent is distilled off. 173 g of crude product are obtained. Fractional distillation gives 112 g (yield 48.3% of theory) of chemically pure ethyl 6-ethoxycarbonyloxy-hexanoate; 75 g thereof can be used as an olfactorily pure product without further treatment.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Cl:32]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Cl:32][C:23]1[CH:22]=[C:21]([CH:13]([C:10]2[CH:9]=[CH:8][C:7]([S:4]([CH:1]3[CH2:2][CH2:3]3)(=[O:6])=[O:5])=[CH:12][CH:11]=2)[CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[NH:25][C:24]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccccn3)[nH]2)cc1)C1CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2cc(Cl)c(-c3ccccn3)[nH]2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.8 %

Procedure:
To a solution of 2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine (200 mg) in tetrahydrofuran (5 mL) was added N-chlorosuccinimide (61.2 mg) at 0° C., and the mixture was stirred overnight at room temperature, and further at 50° C. for 1 day. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (60.0 mg, yield 28%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 471 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([CH:11]([OH:16])[C:12](=[NH:15])[NH:13][OH:14])[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].[C:18](O)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:17])[NH:7][CH:8]([CH:11]([OH:16])[C:12](=[NH:15])[NH:13][O:14][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:9][CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(O)c1ccccc1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(O)C(=N)NO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(NC(=O)OC(C)(C)C)C(O)C(=N)NOC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.2 %

Procedure:
A solution of {1-[hydroxy-(N-hydroxycarbamimidoyl)-methyl]-propyl}-carbamic acid tert-butyl ester (2) (2.5 g, 10 mmol) in dichloromethane (125 ml) was treated with benzoic acid (1.36 g, 11 mmol), EDCI (2.14 g, 11 mmol), HOBT (1.37 g, 10 mmol) and triethylamine (1.35 ml, 11 mmol) and stirred at room temperature overnight. Reaction mixture was washed with saturated sodium bicarbonate solution and then water and dried over Na2SO4. Solvent evaporated under reduced pressure, crude purified by mplc eluting with 1% triethylamine in 2:3 v/v ethyl acetate and heptane mixture to give yellow solid (850 mg); MS: MH+ 352.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[CH2:37]([NH:36][S:33]([C:29]1[CH:28]=[C:27]([NH:26][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:14])[CH:32]=[CH:31][CH:30]=1)(=[O:35])=[O:34])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Nc1cccc(S(=O)(=O)NCc2ccccc2)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=C(Nc1cccc(S(=O)(=O)NCc2ccccc2)c1)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N-benzyl-benzenesulfonamide [CAS No. 303780-52-1] according to general procedure II. Light yellow solid. MS (ISP) 600.1 [(M−H)−]; mp 230° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][OH:11])=[CH:7][CH:8]=2)[CH2:3][NH:2]1.C(N(CC)CC)C.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>O1CCCC1>[CH2:23]([O:22][C:20]([N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[C:6]([CH2:10][OH:11])[CH:5]=2)[CH2:1]1)=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OCc1ccc2c(c1)CNC2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1Cc2ccc(CO)cc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
A mixture of (2,3-dihydro-1H-isoindol-5-yl)-methanol (1.34 g, 9.0 mmol) in anhydrous tetrahydrofuran (50 ml) was warmed gently to aid dissolution and allowed to cool to room temperature. Triethylamine (1.5 ml, 10.8 mmol) was added and the stirred mixture was treated dropwise with benzyl chloroformate (1.35 ml, 9.5 mmol) and stirred at room temperature for 3 hours. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (30 ml) and 2M hydrochloric acid (30 ml). The organic layer was washed with water (30 ml), separated and the solvent removed in vacuo to afford a pink oil that solidified upon standing. The solids were triturated with 10% ethyl acetate in hexane (10 ml), filtered, rinsed with heptane (10 ml) and sucked dry to afford the title compound (2.5 g, 98%) as a pale pink solid. 1H NMR (DMSO-d6) 7.45-7.21 (8H, m), 5.20 (1H, t), 5.17 (2H, s), 4.71 (2H, br s), 4.64 (2H, br s), 4.50 (2H, d). MS: [M+H]+ 284.
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].[Si:13]([O:20][CH:21]([CH2:28][CH2:29][CH3:30])[CH2:22][C:23](OCC)=[O:24])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C1COCC1>[CH3:9][O:8][P:7]([CH2:6][C:23](=[O:24])[CH2:22][CH:21]([O:20][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15])[CH2:28][CH2:29][CH3:30])(=[O:12])[O:10][CH3:11]
Reactant: CCCC(CC(=O)OCC)O[Si](C)(C)C(C)(C)C
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC(CC(=O)CP(=O)(OC)OC)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Yield: 36.2 %

Procedure:
n-Butyllithium (6.8 mL of a 1.6M solution in THF, 10.94 mmol) was added to a solution of dimethyl methylphosphonate (1.2 mL, 10.94 mmol) in THF (22 mL) at −78° C. After 0.5 h a solution of the ester 2 (2.0 g, 7.29 mmol) in THF (4 mL) was added. The reaction solution was allowed to warm to room temperature overnight on its own accord. After 16 h the reaction was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The organic portion was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 2:1 hex/EtOAc followed by 1:1 hex/EtOAc) afforded 0.93 g (36%) of phosphonate 3 (see Scheme 1).
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][Cl:25])=[CH:22][CH:21]=1>CCO>[ClH:25].[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][S:18][C:9]2[NH:8][C@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C@H:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:10]=2)=[CH:22][CH:21]=1
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Reactant: ClCc1ccc(Br)cc1
Solvent: CCO
Product: Brc1ccc(CSC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)cc1
Product: Cl
Temperature: 25 °C
Yield: 80.2 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 4-bromobenzyl chloride (327 mg, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 290 mg of the product 237. 1H NMR (DMSO-d6) δ 11.30 (s, 2 H), 7.65 (d, 2 H), 7.58 (d, 2 H), 7.15-6.95 (m, 6 H), 6.90-6.65 (m, 4 H), 5.78 (s, 2 H), 4.80 (s, 2 H); MS: m/z 424 (M++1).