Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:21])=[N:11][C:10]=1[C:22]([OH:24])=O)=O)(C)(C)C.[NH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][CH2:35][C@H:34]([NH:38]C(=O)OC(C)(C)C)[CH2:33]1>>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=2[Cl:20])=[N:11][C:10]=1[C:22]([NH:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][CH2:35][C@H:34]([NH2:38])[CH2:33]1)=[O:24]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(Cl)cccc2Cl)nc1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2N)C1
Product: Nc1sc(-c2c(Cl)cccc2Cl)nc1C(=O)Nc1cnccc1N1CCC[C@H](N)C1

Procedure:
Followed the procedure as described in EXAMPLE 1, starting with 5-(tert-butoxycarbonylamino)-2-(2,6-dichlorophenyl)thiazole-4-carboxylic acid and (S)-tert-butyl 1-(3-aminopyridin-4-yl)piperidin-3-ylcarbamate. Obtained the desired product as a white solid (9 mg). 1H NMR (500 MHz, DMSO) δ 9.21 (s, 1H), 8.18 (d, J=5.3 Hz, 1H), 7.69-7.60 (m, 2H), 7.56 (dd, J=8.9, 7.3 Hz, 3H), 7.04 (d, J=5.3 Hz, 1H), 3.08 (d, J=8.1 Hz, 1H), 2.97 (d, J=11.9 Hz, 1H), 2.79 (d, J=9.0 Hz, 1H), 2.56 (dd, J=21.5, 11.0 Hz, 1H), 2.48-2.41 (m, 1H), 1.66 (d, J=14.0 Hz, 2H), 1.54 (d, J=10.1 Hz, 1H), 1.11 (d, J=9.8 Hz, 1H). ESIMS m/z=463.1 (M+1).
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][NH2:10])[CH:2]=[CH2:3].C(Cl)(Cl)Cl.[CH3:15][NH:16][S:17]([C:20]1[CH:21]=[C:22]([C:30](Cl)=[O:31])[C:23]2[O:28][CH2:27][CH2:26][O:25][C:24]=2[CH:29]=1)(=[O:19])=[O:18]>O>[CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][NH:10][C:30]([C:22]1[C:23]2[O:28][CH2:27][CH2:26][O:25][C:24]=2[CH:29]=[C:20]([S:17](=[O:19])(=[O:18])[NH:16][CH3:15])[CH:21]=1)=[O:31])[CH:2]=[CH2:3]
Reactant: CNS(=O)(=O)c1cc2c(c(C(=O)Cl)c1)OCCO2
Reactant: C=CCN1CCCC1CN
Solvent: ClC(Cl)Cl
Solvent: O
Product: C=CCN1CCCC1CNC(=O)c1cc(S(=O)(=O)NC)cc2c1OCCO2
Yield: 49 %

Procedure:
85 g of levorotatory 1-allyl-2-aminomethyl-pyrrolidine, 610 cm3 of chloroform, and gradually, 178 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride at a temperature of from 5°-10° C. were introduced into a balloon flask provided with an agitator and a thermometer. After agitation of the mixture 1.2 liters of water were added and then chloroform was distilled. The remaining solution was filtered and then the base was precipitated with 70 cm3 of 20% ammonia. The crystals formed were dried off and washed with water. After recrystallization from ethyl acetate, 117 g of levorotatory-N-(1-allyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide was produced (M.P.: 101°-102° C.; yield: 49%).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][CH2:11][OH:12])=[CH:4][C:3]=1[CH3:13].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(O)(C)C>ClCCl>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][CH:11]=[O:12])=[CH:4][C:3]=1[CH3:13]
Reactant: Cc1cc(CCCO)cc(C)c1Br
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CC(C)O
Product: Cc1cc(CCC=O)cc(C)c1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3-(4-bromo-3,5-dimethylphenyl)propan-1-ol (250 mg) in dichloromethane (5 mL) is added at 0° C. 1,1-dihydro-1,1,1-triacetoxy-1,2-benziodoxol-3(1H)-on (Dess-Martin periodinan, 2.7 mL of a 15% solution in dichloromethane). The mixture is stirred for 12 hours at room temperature, cooled to 0° C. and 1,1-dihydro-1,1,1-triacetoxy-1,2-benziodoxol-3(1H)-on (Dess-Martin periodinan, 1.6 mL of a 15% solution in dichloromethane) is added. After stirring for 4 hours isopropanol (5 mL) is added, the mixture is stirred for 15 minutes and the solvents are evaporated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→70:30) to give the title compound. Yield: 120 mg; LC (method 8): tR=0.38 min; Mass spectrum (ESI−): m/z=239 [M−H]−.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@@H:5]([C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[CH2:14][CH2:13]1)=[O:11])[CH2:6][C:7](=[O:9])[NH2:8].[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:34](O)=[O:35])[CH:32]=2)[CH:27]=[CH:26]1>>[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:34]([NH:4][C@@H:5]([C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH:18]4[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]4)[CH2:14][CH2:13]3)=[O:11])[CH2:6][C:7](=[O:9])[NH2:8])=[O:35])[CH:32]=2)[CH:27]=[CH:26]1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: CN1CCC(N2CCN(C(=O)[C@H](N)CC(N)=O)CC2)CC1
Agent: Cl
Product: CN1CCC(N2CCN(C(=O)[C@@H](CC(N)=O)NC(=O)c3ccc4cc[nH]c4c3)CC2)CC1

Procedure:
Using methods substantially equivalent to those described in Method D-1, the titled compound was prepared from 1-(D-asparaginyl)-4-(1-methylpiperidin-4-yl)piperazine trihydrochloride and indole-6-carboxylic acid (45%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([CH2:7][NH:8][C:9](=[O:15])[O:10][CH2:11][CH2:12][O:13][CH3:14])[CH2:2]1.Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([CH3:27])=[CH:24][CH:25]=2)[N:20]=[C:19]([C:28]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=2[OH:35])[N:18]=1.C(N(CC)CC)C>C(Cl)Cl>[F:34][C:33]1[CH:32]=[CH:31][CH:30]=[C:29]([OH:35])[C:28]=1[C:19]1[N:18]=[C:17]([N:1]2[CH2:6][CH2:5][CH2:4][C@@H:3]([CH2:7][NH:8][C:9](=[O:15])[O:10][CH2:11][CH2:12][O:13][CH3:14])[CH2:2]2)[C:26]2[C:21](=[CH:22][C:23]([CH3:27])=[CH:24][CH:25]=2)[N:20]=1
Reactant: COCCOC(=O)NC[C@@H]1CCCNC1
Reactant: Cc1ccc2c(Cl)nc(-c3c(O)cccc3F)nc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOC(=O)NC[C@@H]1CCCN(c2nc(-c3c(O)cccc3F)nc3cc(C)ccc23)C1
Yield: 88.1 %

Procedure:
To a solution of 2-methoxyethyl ((R)-piperidin-3-yl)methylcarbamate (0.24 g, 1.1 mmol) and 2-(4-chloro-7-methylquinazolin-2-yl)-3-fluorophenol (250 mg, 0.865 mmol) in CH2Cl2 was added triethylamine (2.41 mL, 1.73 mmol). After stirring the reaction at room temperature for 2 h, it was quenched with water and then extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0%-10% EtOAc in CH2Cl2 yielded 2-methoxyethyl ((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate (357 mg, 88%). LC/MS: m/z 469.5 (M+H)+ at 2.30 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12]C(=O)C)=[CH:8][C:7]=1[C:16]1[N:17]([CH3:21])[N:18]=[CH:19][CH:20]=1.[OH-].[Na+]>CO.O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[C:16]1[N:17]([CH3:21])[N:18]=[CH:19][CH:20]=1
Reactant: COCCOc1ccc(NC(C)=O)cc1-c1ccnn1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCCOc1ccc(N)cc1-c1ccnn1C
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
To a suspension of N-(4-(2-methoxyethoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenyl)acetamide (289 mg, 1.0 mmol) in MeOH (3 mL) was added a solution of sodium hydroxide (240 mg, 6.0 mmol) in water (0.4 mL) and the mixture was stirred at 160° C. in a microwave oven. After 30 minutes, the mixture was allowed to cool to room temperature, and the solvent was removed under reduced pressure. The residue was taken up in water, and extracted three times with dichloromethane. The extracts were combined, dried with sodium sulfate, filtered, and evaporated to dryness to afford the title compound (231 mg, 93% yield) as a brown oil which was used without further purification. LCMS m/z (%) 248.1 (M+H, 100%). 1H NMR (400 MHz, DMSO-d6) δ 3.19 (s, 3H) 3.48-3.53 (m, 2H) 3.63 (s, 3H) 3.89-3.96 (m, 2H) 4.81 (s, 2H) 6.16 (d, J=1.77 Hz, 1H) 6.48 (d, J=3.03 Hz, 1H) 6.62 (dd, J=8.72, 2.91 Hz, 1H) 6.86 (d, J=8.84 Hz, 1H) 7.39 (d, J=1.77 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:15][CH:16]=2)[N:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:10]=1[CH:29]=[O:30])=[O:8].[CH3:35][Mg+].[Br-]>COCCOC>[F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:15][CH:16]=2)[N:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:10]=1[CH:29]([OH:30])[CH3:35])=[O:8]
Reactant: C[Mg+]
Reactant: CC(C)Oc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C=O)n(Cc3ccccn3)c2c1
Agent: [Br-]
Solvent: COCCOC
Product: CC(C)Oc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)O)n(Cc3ccccn3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-(3,4-difluorobenzyl)-2-formyl-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 105, 102 mg, 0.23 mmol) in 1,2-dimethoxy-ethane (15 ml) was added MeMgBr (1.4 M in toluene-THF, 0.5 ml, 0.70 mmol) at 0° C. The reaction was stirred at room temperature for 2 h and more MeMgBr (1.0 ml, 1.4 mmol) was added. The reaction was stirred at room temperature for another 2 h and was quenched with ice, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[CH3:13][C:14]([O:17][C:18]([NH:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:19])([CH3:16])[CH3:15].C([O-])(O)=O.[Na+]>CS(C)=O>[C:14]([O:17][C:18](=[O:19])[NH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:3]=[C:4]([CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=2)[CH2:23][CH2:22]1)([CH3:16])([CH3:13])[CH3:15]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Cc1cc(F)cc(N)c1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(N2CCC(NC(=O)OC(C)(C)C)CC2)cc(N)c1[N+](=O)[O-]
Temperature: 85 °C
Reaction time: 3 h

Procedure:
5-Fluoro-3-methyl-2-nitro-phenylamine (0.97 g, 5.7 mmol), 4-N-BOC-aminopiperidine (1.60 g, 8.0 mmol), diusopropylethylamine (2.5 ml, 14 mmol) and DMSO (10 ml) are combined and stirred at 85° C. for 3 hours. The reaction mixture was poured on saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The organic layers were washed with water (3×) and brine, dried over Na2SO4 and concentrated. Flash column chromatography on silica (eluent hexanes-ethyl acetate-triethylamine 50-50-1, then 33-66-1) gave the title compound as a yellow solid. (1.57 g, 79%). LCMS (M+H)+ m/z 351 (t=1.55 min.). 1H NMR (500 MHz, CD3OD) δ 6.70 (1H, broad s), 6.22 (1H, d, J=2.5 Hz)), 6.13 (1H, d, J=2.5 Hz), 3.88 (2H, d, J=13.3 Hz), 3.58 (1H, broad s), 2.98 (2H, t, J=11.8 Hz), 2.48 (3H, s), 1.92 (2H, d, J=11.3 Hz), 1.48 (2H, m), 1.45 (9H, s).
Reaction SMILES: [CH2:1]([C:8]1[NH:13][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][N:10]2[C:20](=[O:29])[C:21]([CH2:23][C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)=[N:22][C:9]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([B:38]2[O:42][C:41]([CH3:44])([CH3:43])[C:40]([CH3:46])([CH3:45])[O:39]2)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[CH2:1]([C:8]1[C:9]2[N:10]([C:20]([O:29][CH2:31][C:32]3[CH:33]=[CH:34][C:35]([B:38]4[O:39][C:40]([CH3:46])([CH3:45])[C:41]([CH3:44])([CH3:43])[O:42]4)=[CH:36][CH:37]=3)=[C:21]([CH2:23][C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)[N:22]=2)[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c(Cc2ccco2)nc2c(Cc3ccccc3)[nH]c(-c3ccccc3)cn1-2
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CC1(C)OB(c2ccc(COc3c(Cc4ccco4)nc4c(Cc5ccccc5)nc(-c5ccccc5)cn34)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.6 %

Procedure:
To a solution of 8-benzyl-2-(furan-2-ylmethyl)-6-phenylimidazo[1,2-a]pyrazin-3(7H)-one (50 mg, 0.13 mmol) was added 2-(4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (47 mg, 0.16 mmol), potassium carbonate (27 mg, 0.20 mmol) and potassium iodide (33 mg, 0.20 mmol). The reaction mixture was stirred at room temperature for 1 h and heat to 40° C. until HPLC shows the completion of the reaction. After cooling down, the reaction mixture was extracted with ethyl acetate/water. The organic layer was collected and dried over magnesium sulfate. After evaporation, the residue was purified with flash chromatography to give the product as yellow solid (30 mg, 49%). 1H NMR (300 MHz, CD2Cl2, δ): 7.79-7.23 (m, 18H), 7.32 (d, J=6.0 Hz, 2H), 5.11 (s, 2H), 4.53 (s, 2H), 4.15 (s, 2H), 1.53 (s, 12H); MS (ESI) m/z 597.41.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH2:8])=[CH:5][CH:4]=1.[OH:11][CH2:12][CH2:13][O:14][C:15]1[C:20]([Br:21])=[CH:19][C:18](I)=[CH:17][N:16]=1>>[Br:21][C:20]1[CH:19]=[C:18](/[CH:8]=[CH:7]/[C:6]2[CH:9]=[CH:10][C:3]([NH:2][CH3:1])=[CH:4][CH:5]=2)[CH:17]=[N:16][C:15]=1[O:14][CH2:13][CH2:12][OH:11]
Reactant: OCCOc1ncc(I)cc1Br
Reactant: C=Cc1ccc(NC)cc1
Product: CNc1ccc(/C=C/c2cnc(OCCO)c(Br)c2)cc1

Procedure:
Compound 14b was prepared from 4-methylaminostyrene (0.140 g, 1.05 mmol) and 9b (0.241 g, 0.7 mmol) as a light yellow viscous liquid (0.149 g, 61% yield). 1H NMR δ 8.07 (d, 1H, J=2.1 Hz), 8.03 (d, 1H, J=2.1 Hz), 7.35 (d, 2H, J=8.6 Hz), 6.93 (d, 1H, J=16.3 Hz), 6.74 (d, 1H, J=16.3 Hz), 6.61 (d, 2H, J=8.6 Hz), 4.57-4.52 (m, 2H), 3.99 (br s, 2H), 3.18 (br s, 1H), 2.88 (s, 3H). 13C NMR δ 149.6, 143.3, 138.5, 130.1, 130.0, 128.0, 126.0, 118.6, 112.6, 107.7, 69.8, 62.2, 30.7. HRMS calcd for C17H19BrN2O2 (M+), 348.0473; found, 348.0468.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH2:11]([CH2:13][NH2:14])[OH:12].Cl.CN(C)CCCN=C=NCC.N=C=N>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:14][CH2:13][CH2:11][OH:12])=[O:8])=[CH:9][CH:10]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N=C=N
Solvent: CN(C)C=O
Product: Nc1ccc(C(=O)NCCO)cc1
Reaction time: 1 h

Procedure:
A solution of 4-aminobenzoic acid (2.7 g, 20 mmol), ethanolamine (1.4 g, 23 mmol), and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (4.19, 21 mmol) in dimethylformamide (60 ml) was stirred overnight at room temperature. More carbodiimide (0.3 g, 2 mmol) was added and after stirring for one hour the reaction mixture was concentrated in vacuo onto silica gel (15 g). Purification by chromatography on silica gel (125 g) eluting with methanol:methylene chloride (3:97 to 1:19) and recrystallization from methanol:ethyl acetate gave, after drying under high vacuum, 4-amino-N-(2-hydroxyethyl)benzamide (1.65 g) as a white solid. 1H NMR (DMSO-d6, 300 MHz) δ: 3.26 (q, J=6 Hz, 2H, NCH2), 3.46 (q, J=6 Hz, 2H, OCH2), 4.68 (t, J=5.5, 1H, OH), 5.58 (br s, 2H, NH2), 6.51 (d, J=8.5 Hz, 2H, Ar), 7.56 (d, J=8.5 Hz, 2H, Ar), 7.94 (br t, J=5.4 Hz, 1H, CONH). Mass spectrum (CI-CH4): 181 (M+1, 100%). Anal. Calculated for C9H12N2O2 : C, 59.99; H, 6.71; N, 15.55. Found: C, 60.05; H, 6.72; N, 15.55.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:21]=[C:22]([O:24][C@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:23]=1)[C:12]([NH:14][C:15]1[CH:19]=[CH:18][N:17]([CH3:20])[N:16]=1)=[O:13])C1C=CC=CC=1>C(O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:21]=[C:22]([O:24][C@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:23]=1)[C:12]([NH:14][C:15]1[CH:19]=[CH:18][N:17]([CH3:20])[N:16]=1)=[O:13]
Reactant: COC[C@@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C)n2)c1
Solvent: CCO
Product: COC[C@@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.2 %

Procedure:
3-(Benzyloxy)-5-[(1R)-2-methoxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (4.23 g, 0.011 mol) was dissolved in ethanol (35 mL) and THF (35 mL) and the flask evacuated and purged with argon (3 times). 10% Palladium on carbon (0.42 g) was added and the flask further evacuated and finally purged with hydrogen gas. The reaction mixture was stirred at ambient temperature for 20 hours until completion. The reaction mixture was evacuated and purged with nitrogen (3 times). The catalyst was filtered off through celite and the filtrate concentrated in vacuo to give the desired compound (2.86 g)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1O>>[F:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[O:29][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(F)cc3)CC2)c1
Reactant: Oc1cc(F)ccc1F
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3cc(F)ccc3F)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 2,5-difluorophenol: ESMS m/e: 511.5 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][C@H:14]1[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[C@H:16]([C:32]([OH:34])=[O:33])[CH2:15]1>O1CCCC1>[CH3:8][S:9]([O:13][C@H:14]1[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)=[O:20])[C@H:16]([C:32]([OH:34])=[O:33])[CH2:15]1)(=[O:11])=[O:10]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.67 h

Procedure:
12.20 ml of triethylamine and 6.81 ml of methanesulfonyl chloride were added, whilst ice-cooling, to a solution of 12.41 g of trans-4-hydroxy-1-(4-nitro-benzyloxycarbonyl)-L-proline in 100 ml of dry tetrahydrofuran, and the resulting mixture was stirred at the same temperature for 40 minutes. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was mixed with 350 ml of ethyl acetate and 50 ml of 1N aqueous hydrochloric acid. The mixture was then stirred at room temperature for 2.5 hours, after which the organic layer was separated and washed three times with an aqueous solution of sodium chloride; it was then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, to give 12.57 g of the title compound, as a powder.
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[C:24]([C:26]1[CH:34]=[CH:33][C:29]([N:30]([CH3:32])[CH3:31])=[CH:28][CH:27]=1)#[CH:25]>>[CH3:31][N:30]([CH3:32])[C:29]1[CH:33]=[CH:34][C:26]([C:24]2[N:3]=[N:2][N:1]([CH:4]3[CH2:23][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[CH:25]=2)=[CH:27][CH:28]=1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Reactant: C#Cc1ccc(N(C)C)cc1
Product: CN(C)c1ccc(-c2cn(C3CCc4c(CC(=O)O)c5ccccc5n4C3)nn2)cc1

Procedure:
The title compound was prepared using procedures described in EXAMPLE 1 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate and 4-ethynyl-N,N-dimethylaniline. MS (+ESI) m/z: 416.2.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)C.C=O.C(O)(=O)C.[NH3:19]>CO>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([NH2:19])=[O:3])=[CH:6][CH:7]=1
Reactant: N
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: C=O
Solvent: CO
Solvent: CC(=O)O
Product: NC(=O)c1ccc(O)cc1

Procedure:
Parahydroxybenzoic acid ethyl ester is dissolved in methanol, added with formalin and acetic acid to react overnight, added to NH3(aq) to obtain para-hydroxy benzoic amide. This product was added with formalin, acetic acid and N7-bromoethyl 3-isobutyl-1-methylxanthine processed through a Mannich reaction to obtain compound 33. Through purification and then dissolution into methanol, add NaOH and ethyl bromide to gain compound 34. Various substitutions can be made to produce other desired compounds. For example, by replacing ethyl bromide with propyl bromide, compound 35 can be obtained. By replacing theophylline with IBMX, compounds 36, 37, and/or 38 can be obtained.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([CH2:9]Br)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.[F:14][CH:15]([F:18])[CH2:16][NH2:17].CS(C)=O>O>[F:14][CH:15]([F:18])[CH2:16][N:17]1[CH2:2][CH2:3][N:4]2[N:5]=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[C:8]2[CH2:9]1
Reactant: O=[N+]([O-])c1cc(CBr)n(CCBr)n1
Reactant: NCC(F)F
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc2n(n1)CCN(CC(F)F)C2
Temperature: 120 °C
Yield: 79.9 %

Procedure:
A sealed tube equipped with a magnetic stirrer was charged with 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole 124c (632 mg, 2.0 mmol), 2,2-difluoroethanamine (486 mg, 6.0 mmol), and DMSO (5 mL). It was heated at 120° C. for 2 h. The mixture was cooled to room temperature and diluted with water (20 mL). The resulting mixture was extracted with ethyl acetate (3×20 mL). The combiner organic layer was dried and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 50:1 dichloromethane/methanol to afford 135a (371 mg, 80%) as a yellow solid. MS-ESI: [M+H]+ 233.2
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[C:6]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)[CH:5]=[CH:4]1.[O:27]1[CH2:32][CH2:31][CH:30]([C:33](O)=[O:34])[CH2:29][CH2:28]1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[C:6]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:33]([CH:30]3[CH2:31][CH2:32][O:27][CH2:28][CH2:29]3)=[O:34])[CH2:24][CH2:25]2)[CH:5]=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2ccoc3cccc2-3)CC1
Reactant: O=C(O)C1CCOCC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2ccoc3cccc2-3)CC1)C1CCOCC1

Procedure:
The title compound, off-white solid (87 mg, 78%), MS (ISP) m/z=439.4 [(M+H)+], mp 217° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-4-yl-piperidin-1-yl)-ethyl]-cyclohexyl-amine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and tetrahydropyran-4-yl-carboxylic acid.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[C:10](Br)=[CH:11][CH:12]=[CH:13][C:6]=2[NH:5][C:4](=[O:15])[CH2:3]1.[C-:16]#[N:17].[Na]>CN(C)C=O.O>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[C:10]([C:16]#[N:17])=[CH:11][CH:12]=[CH:13][C:6]=2[NH:5][C:4](=[O:15])[CH2:3]1
Reactant: [C-]#N
Reactant: CN1CC(=O)Nc2cccc(Br)c2C1=O
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CC(=O)Nc2cccc(C#N)c2C1=O
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 42.4 %

Procedure:
2.3 g of 3,4-dihydro-4-methyl-6-bromo-2H-1,4-benzodiazepine-2,5(1H)-dione (U.S. Pat. No. 4,352,817 ex.9) and 1.26 g of cupro cyanide was dissolved in 5 ml dimethyl formamide. This mixture was heated to 110° C. for 30 minutes. This mixture was then cooled to 50° C. and 2.4 g sodium in 6 ml water was added. The resulting mixture was then stirred for 10 minutes, whereafter 30 ml water was added. This mixture was extracted two times with 25 ml ethyl acetate. The organic phase was dryed with calcium chloride. After filtration the organic solution was evaporated in vacuo to give 0.78 g of the title compound. M.p. 261°-69° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5](=[C:7]1[CH2:12][C@@H:11]2[C@@H:9]([CH2:10]2)[C:8]1=O)[O-])[CH3:2].[K+].[Cl:16][C:17]1[N:18]=[N:19][C:20]([NH:23][NH2:24])=[CH:21][CH:22]=1>>[CH2:1]([O:3][C:4]([C:5]1[C:7]2[CH2:12][C@H:11]3[CH2:10][C@H:9]3[C:8]=2[N:23]([C:20]2[N:19]=[N:18][C:17]([Cl:16])=[CH:22][CH:21]=2)[N:24]=1)=[O:14])[CH3:2]
Reactant: CCOC(=O)C([O-])=C1C[C@H]2C[C@H]2C1=O
Reactant: NNc1ccc(Cl)nn1
Agent: [K+]
Product: CCOC(=O)c1nn(-c2ccc(Cl)nn2)c2c1C[C@H]1C[C@@H]21

Procedure:
The title compound was prepared in a manner similar to that described in Method C using potassium 2-ethoxy-2-oxo-1-((1R,5R)-2-oxobicyclo[3.1.0]hexan-3-ylidene)ethanolate and 3-chloro-6-hydrazinylpyridazine. LCMS m/z=305.2 [M+H]+.