Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]2[CH:10]=[C:11]([O:16][CH2:17][C@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[CH3:23])[CH:12]=[N:13][C:14]=2[Cl:15])=[CH:3][CH:2]=1>CO>[ClH:15].[ClH:15].[ClH:15].[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]2[CH:10]=[C:11]([O:16][CH2:17][C@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[CH3:23])[CH:12]=[N:13][C:14]=2[Cl:15])=[CH:3][CH:2]=1
Reactant: CN1CCC[C@@H]1COc1cnc(Cl)c(C=Cc2ccncc2)c1
Solvent: CO
Product: CN1CCC[C@@H]1COc1cnc(Cl)c(CCc2ccncc2)c1
Product: Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 105.5 %

Procedure:
A sample of 5-(2-(4-pyridinyl)ethenyl)-6-chloro-3-(1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine from Example 82 (85 mg) was dissolved in MeOH. To this solution was added PdlC (9.5 mg), and the mixture was stirred under H2 for 16 hours at room temperature. The catalyst was filtered off, and the solvent was removed under vacuum. The residue was chromatographed on a silica gel column, eluting with CH2Cl2:MeOH 100:3-100:10 to afford to give the free base of the title compound (30 mg). MS (CI/NH3) m/z 332 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 1.65 (m, 2H), 1.80 (m, 1H), 2.0 (m, 1H), 2.32 (m, 1H), 2.47 (s, 3H), 2.64 (m, 1H), 2.96 (m, 4H), 3.12 (m, 1H), 3.90 (m, 2H), 6.98 (m, 1H), 7.12 (m, 2H), 7.96 (m, 1H), 8.50 (m, 2H). The base was converted to the salt by treatment with HCl in Et2O to give the title compound. mp 236-238° C. MS (CI/NH3) m/z 332 (M+H)+. 1H NMR (D2O, 300 MHz) δ: 1.98-2.23 (m, 3H), 2.38 (m, 1H), 3.01 (s, 3H), 3.17 (m, 2H), 3.25 (m, 3H), 3.74 (m, 1H), 3.90 (m, 1H), 4.27 (dd, J=7.1, 11.2, 1H), 4.44 (dd, J=3.10, 11.2, 1H), 7.36 (d, J=3.0, 1H), 7.70 (d, J=8.4, 2H), 8.01 (d, J=3.0, 1H), 8.56 (d, J=6.1, 2H). Anal. Calcd for C18H22N3OCl.3 HCl: C, 49.00; H, 5.71; N, 9.52. Found: C, 48.94; H, 5.85; N, 9.23. [α]25D=+8.64° (c 0.94, MeOH).
Reaction SMILES: [NH2:1][C:2]1[N:12]=[C:11]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:20]Cl>C(O)(=O)C>[NH2:1][C:2]1[N:12]=[C:11]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:10]([Cl:20])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1ccc(NC(=O)C(C)(C)C)nc1N
Reactant: ClCl
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(Cl)c(NC(=O)C(C)(C)C)nc1N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76 %

Procedure:
To a solution of ethyl 2-amino-6-[(2,2-dimethylpropanoyl)amino]nicotinate (Example 1, METHOD A, Step 1, 805 mg, 3.03 mmol) in acetic acid (15 ml) was added a solution of chlorine in acetic acid (0.89 M, 8.5 mL, 7.6 mmol), and the mixture was stirred at room temperature for 15 min. The solvent was removed in vacuo. The obtained residue was taken up in ethyl acetate (150 mL) and washed with saturated sodium bicarbonate, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on a column of silica gel eluting with ethyl acetate/pentane (1:2) to give 685 mg (76%) of the title compound as a white crystal.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](OC)=O)[CH2:13][C:12]1=C)([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH2:22]([OH:26])CCC>>[C:7]([O:6][C:4]([N:11]1[CH2:12][CH2:13][C:14]2([NH:3][NH:2][C:22](=[O:26])[CH2:17]2)[CH2:15][CH2:16]1)=[O:5])([CH3:8])([CH3:9])[CH3:10]
Reactant: NN
Reactant: C=C1CC(C(=O)OC)CCN1C(=O)OC(C)(C)C
Reactant: CCCCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)NN2
Temperature: 120 °C
Reaction time: 15 h
Yield: 63 %

Procedure:
A solution of hydrazine monohydrate (5.28 mL, 108.8 mmol) in n-butanol (20 mL) was added dropwise to a solution of N-BOC-4-methoxycarbonyl-methylenepiperidine (1.39 g, 5.44 mmol) in n-butanol (120 mL) at rt. The mixture was stirred for 15 h at 120° C. and the mixture allowed to cool to rt. The solvent was removed by evaporation under reduced pressure, the residue partitioned between ethyl acetate and water and the organic layer dried over sodium sulphate, filtered and evaporated to dryness. Purification of the residue by silica gel column chromatography, eluting with a stepwise gradient of 3-6% methanol in dichloromethane, afforded the desired compound (0.88 g, 63%) as white solid.
Reaction SMILES: [Br:1][C:2]1(C(OC)=O)[CH:11]=[CH:10][CH:9]=[C:4]([C:5](OC)=[O:6])[CH2:3]1.[BH4-].[Na+].[CH3:18][OH:19].Cl.[O:21]1CCC[CH2:22]1>>[Br:1][C:2]1[CH:11]=[C:10]([CH:9]=[C:4]([CH2:5][OH:6])[CH:3]=1)[C:18]([O:21][CH3:22])=[O:19]
Reactant: C1CCOC1
Reactant: CO
Reactant: COC(=O)C1=CC=CC(Br)(C(=O)OC)C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: COC(=O)c1cc(Br)cc(CO)c1

Procedure:
In 25 ml of tetrahydrofuran, was dissolved 10.00 g of dimethyl 3-bromoisophthalate. 1.66 g of sodium borohydride was added to the above solution and thereby a suspension was obtained. A mixed solution of 7.4 ml of methanol and 25 ml of tetrahydrofuran was slowly dropped into the resulting suspension. After completing the dropping, the reaction solution was refluxed for 30 minutes. A 1 M hydrochloric acid was added to the solution to quench the reaction. The resulting solution was extracted with ethyl acetate, and the organic layer was dried over magnesium sulfate. The solvent was removed under reduced pressure to afford 9.30 g of the title compound as a colorless oil quantitatively.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]=[CH2:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=C(C#N)C=1.[OH:23]O>C[Re](=O)(=O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]2[CH2:14][O:23]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OO
Reactant: C=C[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: C[Re](=O)(=O)=O
Agent: N#Cc1cccnc1
Product: CC(C)(C)OC(=O)N1CC[C@H](C2CO2)C1

Procedure:
To (R)-3-vinylpyrrolidine-1-carboxylic acid t-butyl ester (6.1 g, 30.8 mmol, 1.0 eq.) was added 3-pyridinecarbonitrile (320 mg, 3.1 mmol, 0.1 eq.) and methyltrioxorhenium (VII) (192 mg, 769 μmol, 0.025 eq.). The mixture was stirred until homogeneous. 30% Hydrogen peroxide (33:77, hydrogen peroxide:H2O, 4.1 mL, 1.3 eq.) was added, and the mixture was placed in a ice water bath and stirred for 2 hours. Additional methyltrioxorhenium (VII) (50 mg) was added. The organic layer was collected and washed with a saturated sodium metabisulfite solution under an ice bath. The material was then washed with saturated aqueous NaCl. The organic layer was collected, dried over Na2SO4, filtered, and concentrated. The peroxide layer was carefully quenched by adding ice followed by adding saturated sodium metabisulfite solution dropwise at 0° C. The crude product was purified by column chromatography (0-100% EtOAc in hexanes) to give (S)-3-oxiranylpyrrolidine-1-carboxylic acid t-butyl ester as a yellowish oil (4.2 g).
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[OH:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=2)=[CH:23][CH:22]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:18][O:17][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][O:20][C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:28]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)=[O:35])=[CH:25][CH:26]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: O=C(Nc1ccc(O)cc1)c1cccnc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccc(NC(=O)c3cccnc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and N-(4-hydroxy-phenyl)-nicotinamide via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a white solid. MS (ES) for C24H24N2O6 [M+H]+: 437.3.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]([F:16])([F:15])[C:9]([CH3:14])([CH3:13])[C:10](O)=[O:11].C[N:18](C=O)C>C(Cl)Cl>[F:7][C:8]([F:16])([F:15])[C:9]([CH3:14])([CH3:13])[C:10]([NH2:18])=[O:11]
Reactant: CC(C)(C(=O)O)C(F)(F)F
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(C)(C(N)=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (140.8 mmol) was added dropwise to a solution of 3,3,3-trifluoro-2,2-dimethyl-propionic acid [889940-13-0] (128 mmol) in CH2Cl2 (128 mL) at 0° C. Added a few dr DMF until gas evolution was observed and then continued stirring for 30 min. After warming to rt and stirring overnight, the reaction mixture was concentrated (40° C., 00 mbar). The residue was dissolved in THF (128 mL), cooled to 0° C. and then slowly treated with a solution of concentrated aqueous ammonia (64 mL). After stirring at 0° C. for 30 min and then at rt for 4 h, the reaction mixture was concentrated to half its volume to give a thick white suspension. After filtering and drying, the title compound was obtained as a white solid. ESI-MS: [M+H]+ 156.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:15]2[NH:14][C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:7]=2[C:6]([CH3:16])=[C:5]2[CH:17]=[N:18][CH:19]=[CH:20][C:4]=12.CC(C)=O.[CH3:25][N:26]=[C:27]=[O:28]>N1C=CC=CC=1>[CH3:25][NH:26][C:27](=[O:1])[OH:28].[OH:1][CH2:2][C:3]1[C:15]2[NH:14][C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:7]=2[C:6]([CH3:16])=[C:5]2[CH:17]=[N:18][CH:19]=[CH:20][C:4]=12
Reactant: CN=C=O
Agent: Cc1c2cnccc2c(CO)c2[nH]c3ccccc3c12
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CNC(=O)O

Procedure:
To a solution of 400 mg (1.53 mmol) of the carbinol 25 in 25 mL of dry pyridine and 20 mL of reagent grade acetone there was added 900 uL of MeNCO. The solution was magnetically stirred at room temperature in a stoppered flask until all the starting alcohol had disappeared as judged by TLC (ca. 3 days). The solvents were removed in vacuo, and the residue was crystallized from EtOAc-CH2Cl2 -MeOH to give 152 mg of the desired carbamate, mp 213°-214.5° C. The filtrate was concentrated to dryness and the remaining solid was flash chromatographed to give an additional 145 mg of material of similar purity: wt 307 mg (61%); NMR (Me2SO-d6) 11.62 (s, 1 H), 9.71 (s, 1 H), 8.46 (d, 1 H), 839 (d, 1 H), 7.97 (d, 1 H), 7.61-7.54 (m, 2 H), 7.32-7.29 (m, 1 H), 7.04 (d, 1 H), 5.77 (s, 2 H), 3.34 (s, 3 H), 2.60 (s, 3 H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)[CH2:5][CH:4]1[CH2:6]O.S(Cl)(Cl)=O>ClC(Cl)C>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:3]23[CH2:5][CH:4]2[CH2:6][NH:1][CH2:2]3)=[CH:9][CH:10]=1
Reactant: NCC1(c2ccc(Br)cc2)CC1CO
Solvent: O=S(Cl)Cl
Solvent: CC(Cl)Cl
Product: Brc1ccc(C23CNCC2C3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [2-aminomethyl-2-(4-bromo-phenyl)-cyclopropyl]-methanol (9.49 g, 37.02 mmol) in dichloroethane (120 mL), was added thionylchloride (3.2 mL, 44.4 mmol) at 0° C. and stirred for 2 h at r.t. After completion of the reaction as indicated by TLC, the reaction mixture was quenched with water (30 mL) at 0° C. Dichloroethane layer was separated from the acidic layer and discarded. The acidic layer was neutralized with sodium bicarbonate at 0° C. till pH=8 and extracted with 5% methanol in DCM (3×300 mL). The combined organic layers were dried over anhydrous sodium sulphate and concentrated to yield the title compound in crude form (5.20 g, 59%) as white gel, which was used as such in the next step.
Reaction SMILES: [C:1]([S:4][CH3:5])(=[NH:3])[NH2:2].[C:6](Cl)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1.O>[C:6]([NH:3]/[C:1](/[S:4][CH3:5])=[N:2]/[C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CSC(=N)N
Solvent: C1CCOC1
Solvent: O
Product: CS/C(=N\C(=O)c1ccccc1)NC(=O)c1ccccc1

Procedure:
To a stirred solution of methyl carbamimidothioate (0.901 g, 10 mmol) in 10 ml of THF were added TEA (6.97 ml, 50.0 mmol) and benzoyl chloride (3.48 ml, 30.0 mmol) at r.t. The reaction was stirred for over night. The reaction mixture was diluted with water (20 ml) and the resulting precipitates were collected by filtration. The filter cake was washed with water and heptane. It was dried by suction in air for 4 hours to yield (Z)-methyl N,N′-dibenzoylcarbamimidothioate. After the filtration, it was pure by LCMS. It was carried on to the next step. LCMS method A, (M+H)+299.1, ret T=1.66 min.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][C:25]1[N:32]2[C:28]([S:29][CH:30]=[CH:31]2)=[N:27][C:26]=1[C:33](O)=[O:34]>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:26]2[N:27]=[C:28]3[N:32]([C:25]=2[CH3:24])[CH:31]=[CH:30][S:29]3)=[O:34])=[O:10])[N:12]=1
Reactant: Cc1c(C(=O)O)nc2sccn12
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2nc3sccn3c2C)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 5-Methyl-imidazo[2,1-b]thiazole-6-carboxylic acid. LC-MS (basic): tR=0.84 min; [M+H]+=491.9.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:30][CH3:31])[CH2:23][CH2:24][CH:25]1[CH2:29][CH2:28][NH:27][CH2:26]1)[CH3:21]>C(OCC)(=O)C.CO>[CH2:30]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][CH:25]1[CH2:29][CH2:28][N:27]([C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:26]1)[CH3:31]
Reactant: CCN(CC)CCC1CCNC1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Solvent: CCOC(C)=O
Solvent: CO
Product: CCN(CC)CCC1CCN(C(=O)N2c3ccccc3C(=O)Nc3cccnc32)C1
Yield: 13 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 3-[2-(diethylamino)ethyl]pyrrolidine in a yield of 13% of theory. Colourless crystals, m.p. 137°-138° C. (from ethyl acetate/methanol 98/2 v/v).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][O:20][C:21]4[CH:25]=[CH:24][O:23][N:22]=4)[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:4]1.Cl[C:29]([O:31][CH3:32])=[O:30].CCCC(C)C>C(OCC)C>[CH3:32][O:31][C:29]([NH:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][O:20][C:21]4[CH:25]=[CH:24][O:23][N:22]=4)[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:4]1)=[O:30]
Reactant: N[C@H]1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCCC(C)C
Solvent: CCOCC
Product: COC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)C1

Procedure:
Using essentially the technique of Example 113, starting from 3-(4-((3S)-3-amino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one hydrochloride salt (170 mg, 0.43 mmol) and methyl chloroformate gave the desired product (114 mg) after trituration with diethyl ether and isohexane.
Reaction SMILES: [N:1]1([CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]2[CH:8]=[C:9]([NH2:14])[C:10]([NH2:13])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(O)(=O)C.[N:25]([O-])=O.[Na+].C(=O)([O-])O.[Na+]>O>[N:1]1([CH:6]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:7]2[CH:12]=[CH:11][C:10]3[NH:13][N:25]=[N:14][C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=N[O-]
Reactant: Nc1ccc(C(c2ccccc2)n2ccnc2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: c1ccc(C(c2ccc3[nH]nnc3c2)n2ccnc2)cc1
Yield: 85.3 %

Procedure:
To a stirred and cooled (5° C.) solution of 5.2 parts of 4-[(1H-imidazol-1-yl)phenylmethyl]- 1,2-benzenediamine in 4.8 parts of acetic acid and 20 parts of water was added a solution of 1.38 parts of sodium nitrite in 10 parts of water. The whole was stirred for 1 hour at room temperature. The reaction mixture was treated with a sodium hydrogen carbonate solution and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from 64 parts of ethyl acetate. The product was filtered off and dried. yielding 4.7 parts (85.3%) of 5-[(1H-imidazol-1-yl)phenylmethyl]-1H-benzotriazole; mp. 178.8° C. (comp. 35). All other compounds listed in Tables I and II can be obtained by analogous methods of preparation.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:33])[C:13](/[CH:23]=[CH:24]/[P:25](=[O:32])([O:29]CC)[O:26]CC)=[CH:14][N:15]3[CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:10][C:9]=2[F:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:35][Si](C)(C)C.C(O)C>C(Cl)(Cl)Cl>[BrH:35].[CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:33])[C:13](/[CH:23]=[CH:24]/[P:25](=[O:26])([OH:32])[OH:29])=[CH:14][N:15]3[CH:18]([CH2:19][CH3:20])[CH2:21][CH3:22])=[CH:10][C:9]=2[F:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOP(=O)(/C=C/c1cn(C(CC)CC)c2cc(NC3CCCCC3)c(F)cc2c1=O)OCC
Reactant: C[Si](C)(C)Br
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: Br
Product: CCC(CC)n1cc(/C=C/P(=O)(O)O)c(=O)c2cc(F)c(NC3CCCCC3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
200 mg of diethyl {(E)-2-[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]vinyl}phosphonate was dissolved in 2.0 ml of chloroform, and 0.4 ml of bromotrimethylsilane was added, followed by overnight stirring at room temperature. Ethanol was added to the reaction mixture, followed by concentration under a reduced pressure. Ethyl acetate was added to the resulting residue, and the insoluble materials were collected by filtration to obtain 120 mg of {(E)-2-[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]vinyl}phosphonic acid hydrobromide.
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5](Br)[N:4]([CH2:11][CH2:12][OH:13])[N:3]=1.[CH2:14]([CH2:16][NH2:17])[OH:15].O>C(O)C>[Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([NH:17][CH2:16][CH2:14][OH:15])[N:4]([CH2:11][CH2:12][OH:13])[N:3]=1
Reactant: NCCO
Reactant: O=[N+]([O-])c1c(Br)nn(CCO)c1Br
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1c(Br)nn(CCO)c1NCCO
Yield: 73.4 %

Procedure:
1.5 g (4.8 mmoles) of 3,5-dibromo-1-(2'-hydroxyethyl)-4-nitropyrazole are heated in a solution of 0.58 g (9.6 mmoles) ethanolamine in 30 ml ethanol for 15 hours at 80° C. After cooling, 50 ml of water are added to the reaction mixture which is then extracted three times with 70 ml of acetic acid ethyl ester. 200 ml n-hexane are added to the purified extraction solutions and the solvent mixture is vacuum distilled to a third of its original amount. Once again, n-hexane is added until the solution becomes cloudy. The crystallized product is then collected by filtration and washed with n-hexane (10 to 20 ml). 1.04 g (74 percent of theory) of 3-bromo-1-(2'-hydroxyethyl)-5-(2'-hydroxyethyl)amino-4-nitropyrazole are obtained in the form of bright yellow crystals with a melting point of 132° to 134° C.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](=[O:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([Si](C)(C)C)([F:22])[F:21].[F-].[Cs+].C1[CH2:33][O:32]CC1>>[CH:1]([N:14]1[CH2:17][C:16]([C:20]([F:22])([F:21])[F:19])([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[C:33]([OH:32])([C:20]([F:22])([F:21])[F:19])=[O:18]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: C1CCOC1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Cs+]
Agent: [F-]
Product: O=C(O)C(F)(F)F
Product: OC1(C(F)(F)F)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-benzhydryl-azetidin-3-one (400 mg, 1.69 mmol) in THF (5 mL), trifluoromethyltrimethylsilane (360 mg, 2.53 mmol) and cesium fluoride(390 mg, 2.57 mmol) were added. The reaction mixture was stirred at rt. for 1 hr. Then it was quenched with 5 mL saturated NH4Cl solution and tetrabutylammonium fluoride (200 mg) was added. The resulting reaction mixture was stirred at rt. for three days. It was then extracted with ether (3×20 mL). The organic layers were combined, dried (MgSO4) and concentrated to give an orange oil as crude product. It was then purified by Prep.HPLC column to afford a white solid as final product as TFA salt. (350 mg, 49% yield). Retention time: 1.442 min. 1H NMR (500 MHz, MeOD) δ ppm 3.92 (d, J=11.29 Hz, 2 H) 4.35 (d, J=11.60 Hz, 2 H) 5.44 (s, 1 H) 7.34-7.55 (m, 10 H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[N:11]1[CH2:22][CH2:21][C:14]2([C:19](=[O:20])[NH:18][CH2:17][CH2:16][CH2:15]2)[CH2:13][CH2:12]1.C1COCC1.Br[CH2:29][C:30]1[C:39]2[O:38][CH2:37][CH2:36][O:35][C:34]=2[CH:33]=[CH:32][CH:31]=1>[NH4+].[Cl-]>[O:35]1[CH2:36][CH2:37][O:38][C:39]2[C:30]([CH2:29][N:18]3[CH2:17][CH2:16][CH2:15][C:14]4([CH2:21][CH2:22][N:11]([C:2]5[CH:3]=[N:4][C:5]6[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=6)[N:1]=5)[CH2:12][CH2:13]4)[C:19]3=[O:20])=[CH:31][CH:32]=[CH:33][C:34]1=2
Reactant: BrCc1cccc2c1OCCO2
Reactant: O=C1NCCCC12CCN(c1cnc3ccccc3n1)CC2
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C1N(Cc2cccc3c2OCCO3)CCCC12CCN(c1cnc3ccccc3n1)CC2
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 79.9 %

Procedure:
To a solution of 9-quinoxalin-2-yl-2,9-diaza-spiro[5.5]undecan-1-one (50 mg, 0.169 mmol) in THF (2 ml) sodium hydride 95% (6.07 mg, 0.253 mmol) was added and the mixture was stirred for 20 min. Then 5-bromomethyl-2,3-dihydro-benzo[1,4]dioxin (77 mg, 0.337 mmol) was added and the reaction mixture was heated at 50° C. over 18 h. Saturated aqueous NH4Cl solution (50 ml) was added and the reaction mixture was extracted with methylene chloride. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography (EtOAc/hexane 70:30) to yield 60 mg (79%) of the title compound. [1H NMR (600 MHz, DMSO-d6) δ 1.54-1.66 (2H, m) 1.76-1.84 (2H, m) 1.87-1.93 (2H, m) 2.02-2.12 (2H, m) 3.23 (2H, t) 3.39-3.47 (2H, m) 4.20-4.23 (2H, m) 4.24-4.27 (3H, m) 4.27-4.30 (1H, m) 4.41 (2H, s) 6.54 (1H, m) 6.72-6.75 (1H, m) 6.75-6.79 (1H, m) 7.32-7.41 (1H, m) 7.49-7.63 (2H, m) 7.80 (1H, d, J=8.07 Hz), 8.82 (1H, s), LCMS RtD=3.27 min, [M+H]+=445.2].
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:11]=[CH:10][N:9]([C:12]3[N:13]=[C:14]4[C:20]([C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:19][N:18](COCC[Si](C)(C)C)[C:15]4=[N:16][CH:17]=3)[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.O.O.O.C([O-])(=O)C.[Na+]>ClCCl.FC(F)(F)C(O)=O>[N:1]1([C:5]([C:7]2[CH:11]=[CH:10][N:9]([C:12]3[N:13]=[C:14]4[C:20]([C:21](=[O:26])[C:22]([CH3:24])([CH3:23])[CH3:25])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)[CH:8]=2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3ccc(C(=O)N4CCC4)c3)nc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-n3ccc(C(=O)N4CCC4)c3)nc12
Reaction time: 17 h
Yield: 31.2 %

Procedure:
A solution of 1-[2-[3-(azetidine-1-carbonyl)-pyrrol-1-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (0.066 g, 0.137 mmol) in 2 mL of dichloromethane and 1 mL of trifluoroacetic acid was stirred for 5 h then concentrated. The resulting residue was dissolved in 1 mL of ethanol and treated with sodium acetate trihydrate (0.186 g, 1.37 mmol). The mixture was stirred for 17 h, then concentrated. Column chromatography (1->8% MeOH/CH2Cl2) afforded 0.015 g (31%) of 1-{2-[3-(azetidine-1-carbonyl)-pyrrol-1-yl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-2,2-dimethyl-propan-1-one as a yellow solid.