Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([N:15]1[CH2:22][C@@H:21]2[C@@H:17]([CH2:18][N:19]([C:23]3[NH:24][C:25]4[CH:31]=[C:30]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH:29]=[CH:28][C:26]=4[N:27]=3)[CH2:20]2)[CH2:16]1)=O)(C)(C)C>>[ClH:1].[C@@H:17]12[CH2:16][NH:15][CH2:22][C@@H:21]1[CH2:20][N:19]([C:23]1[NH:24][C:25]3[CH:31]=[C:30]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:29]=[CH:28][C:26]=3[N:27]=1)[CH2:18]2
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3nc4ccc(-c5ccccc5)cc4[nH]3)C[C@@H]2C1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc(-c2ccc3nc(N4C[C@H]5CNC[C@H]5C4)[nH]c3c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4N Hydrochloric acid/dioxane solution (1 mL) was added to 2-(3-tert-butoxycarbonyl-cis-3,7-diazabicyclo[3.3.0]oct-7-yl)-5-phenylbenzimidazole (26 mg), followed by stirring at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (26 mg).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[C:9]1([S:15](Cl)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>[OH-].[Na+]>[C:9]1([S:15]([N:1]2[CH2:8][CH2:7][CH2:6][C@H:2]2[C:3]([OH:5])=[O:4])(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@@H]1CCCN1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
To a solution of d/l-proline (2.0 g, 6.8 mmol) in aqueous sodium hydroxide (1M, 34.7 mL) chilled at 0° C., was added phenylsulfonyl chloride (2.21 mL, 17.0 mmol) slowly. The reaction was stirred overnight at room temperature. The reaction mixture was acidified with HCl (20 ml, aqueous, 1 N) and extracted with diethyl ether (2×20 mL). The combined organic extracts were then dried over magnesium sulfate and concentrated under reduced pressure to give the desired N-phenylsulfonyl proline (1.7 g) as a white solid used without any further purification.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:9]([O:16][C:17]([NH:19][CH:20]([CH3:23])[CH2:21][OH:22])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CN=C1>CN(C)C=O>[Si:1]([O:22][CH2:21][CH:20]([NH:19][C:17](=[O:18])[O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(CO)NC(=O)OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(CO[Si](C)(C)C(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 96.6 %

Procedure:
A solution of 13.72 g of t-butyldimethylsilyl chloride in 50 ml of dimethylformamide was added dropwise, whilst ice-cooling, to a mixture of 16.0 g of 2-benzyloxycarbonylaminopropanol (prepared as described in Preparation 7), 12.39 g of imidazole and 150 ml of dimethylformamide. The mixture was then stirred at room temperature for 6.5 hours. At the end of this time, the dimethylformamide was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the resulting residue, which was then extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extract by evaporation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using a 1:6 by volume mixture of ethyl acetate and hexane as the eluent, to give 23.89 g of the title compound, melting at 68.0° C. to 70.2° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[C:7]2[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1.[NH3:23]>O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[Cl:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[Cl:21])[CH2:14][NH:13][C:7]1[C:6]2[C:11](=[C:2]([NH2:23])[CH:3]=[CH:4][CH:5]=2)[N:10]=[C:9]([CH3:12])[CH:8]=1
Reactant: N
Reactant: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(Br)c2n1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(N)c2n1
Yield: 52 %

Procedure:
(8-Bromo-2-methylquinolin-4-yl)-(3,4-dichlorobenzyl)-amine (500 mg, 1.26 mmole), copper(II)sulphate pentahydrate (316 mg, 1.27 mmole) and ammonia (20% in water/ethanol 1:1, 20 mL) were stirred in a microwave oven at 150° C. for 5 hrs. The reaction mixture was dissolved in water and extracted with dichloromethane. The resulting organic phases were dried and purified using silica gel chromatography, eluting with dichloromethane:water 99:1. Precipitation in isopropyl ether gave a brownish solid (220 mg, 52%).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH2:6][CH:5]([C:8](O)=[O:9])[CH2:4][CH2:3]1.S(Cl)([Cl:14])=O>>[CH3:1][C:2]1([CH3:11])[CH2:7][CH2:6][CH:5]([C:8]([Cl:14])=[O:9])[CH2:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: CC1(C)CCC(C(=O)O)CC1
Product: CC1(C)CCC(C(=O)Cl)CC1
Reaction time: 3 h

Procedure:
To 5 g of 4,4-dimethyl-cyclohexylcarboxylic acid was added an excess of thionyl chloride, and the mixture was heated with stirring for 3 hours. After the reaction, the remaining thionyl chloride was distilled off in a vacuum, 10 ml of benzene was added to the residue and the mixture was distilled in a vacuum, giving oily 4,4-dimethylcyclohexylcarbonyl chloride.
Reaction SMILES: [C:1]([C:6]1([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7]1)(=O)[CH2:2][CH2:3][CH3:4].C(O)=O.[CH:20]([NH2:22])=[O:21]>CCOCC>[CH:20]([NH:22][CH:1]([C:6]1([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7]1)[CH2:2][CH2:3][CH3:4])=[O:21]
Reactant: CCCC(=O)C1(c2ccc(Cl)cc2)CCC1
Reactant: NC=O
Solvent: CCOCC
Solvent: O=CO
Product: CCCC(NC=O)C1(c2ccc(Cl)cc2)CCC1

Procedure:
A mixture of the ketone produced as described above (21 g) and 98% formic acid (6 ml) was added over a period of one and a half hours to formamide (15 ml) at 160° C. After completion of the addition the temperature was raised to 180° to 185° C. and maintained in this range for five hours. The mixture was cooled and extracted with chloroform to yield a thick gum which on heating with petroluem ether (b.p. 60°-80°) gave a colourless solid which was recrystallised from petroleum ether (b.p. 60°-80°) to yield N-formyl-1-[1-(4-chlorophenyl)cyclobutyl]butylamine (m.p. 97.5° to 98.5° C.) (Formula I R1 =propyl; R2 =H; R3 =H; R4 =CHO; R5 =4-Cl; R6 =H).
Reaction SMILES: [CH:1]([C:4]1[S:13][C:12]2[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=[C:7]([N:18]3[CH2:23][CH2:22][NH:21][CH:20]([CH2:24][CH2:25][OH:26])[CH2:19]3)[C:6]=2[N:5]=1)([CH3:3])[CH3:2].C=O.[C:29](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(=O)(O)[O-].[Na+]>[CH:1]([C:4]1[S:13][C:12]2[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=[C:7]([N:18]3[CH2:23][CH2:22][N:21]([CH3:29])[C@@H:20]([CH2:24][CH2:25][OH:26])[CH2:19]3)[C:6]=2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)c1nc2c(s1)Nc1ccccc1N=C2N1CCNC(CCO)C1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)c1nc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](CCO)C1
Yield: 35.3 %

Procedure:
Combine 2-[4-(2-Isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-ethanol (0.161 g, 0.433 mmol), formaldehyde (46 μL, 0.563 mmol, 37%), and sodium triacetoxyborohydride (0.138 g, 0.650 mmol) in dichloroethane (15 mL) and stir at room temperature overnight. Dilute the mixture with saturated sodium bicarbonate and extract three times with methylene chloride. Combine the organic layers, dry over sodium sulfate and concentrate under reduced pressure to give the crude product. Purification by flash chromatography, eluting with a step gradient starting with dichloromethane going to 8% 2N ammonia-methanol in dichloromethane gives (S)-2-[4(2-isopropyl-4H-3-thia-1,4,9-triazabenzo[f]azulen-10-yl)-1-methylpiperazin-2-yl]ethanol (0.059 g, 0.153 mmol, 35%) as a yellow oil. Mass spectrum (APCI): m/z=386.4 (M+1). Isolate clean product as the corresponding dihydrochloride in the following manner: dissolve the yellow oil in ethanol (5 mL) and add a solution of about 5 equivalents of HCl in ethanol (5 mL). Evaporate the mixture to obtain (S)-2-[4-(2-isopropyl-4H-3-thia-1,4,9-triazabenzo[f]azulen-10-yl)-1-methylpiperazin-2-yl]ethanol dihydrochloride.
Reaction SMILES: [C:1]1([PH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([O-:11])OCC)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:18][C:19]([F:23])([F:22])[CH2:20]I>>[F:18][C:19]([F:23])([F:22])[CH2:20][P:7](=[O:11])([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: FC(F)(F)CI
Reactant: CCO[PH]([O-])(c1ccccc1)c1ccccc1
Product: O=P(CC(F)(F)F)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of ethyl diphenylphosphonite (1.98 g; 5.8 mmol) and 2,2,2-trifluoroethyl iodide (6.1 g; 29 mmol) was stirred at room temperature under nitrogen for 24 hrs. The excess reagents were removed under vacuum. The residue was purified on silica gel using a 0-100% hexane-ethyl acetate gradient to give the target as a white powder (800 mg; 49%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[SH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14]>C(O)C>[C:13]([C:12]1[CH:11]=[C:10]([S:9][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:18]=[CH:17][CH:16]=1)([OH:15])=[O:14]
Reactant: Clc1ccnc(Cl)n1
Reactant: O=C(O)c1cccc(S)c1
Solvent: CCO
Product: O=C(O)c1cccc(Sc2ccnc(Cl)n2)c1

Procedure:
4-(3-Carboxyphenylsulphanyl)-2-chloropyrimidine was prepared by heating a solution of 2,4-dichloropyrimidine (2.97 g, 19.9 mmol) and 3-mercaptobenzoic acid (3.07 g, 1 9.9 mmol) in ethanol (50 ml) at reflux for 1 h. On cooling to 0°, the resulting precipitate was collected and dried to give the desired material (3.38 g) as a white solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:17]([Cl:18])=[CH:16][C:6]([C:7]([NH:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:8])=[C:5]([O:19][CH3:20])[CH:4]=1.Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].Cl>CN(C)C=O>[ClH:18].[NH2:2][C:3]1[C:17]([Cl:18])=[CH:16][C:6]([C:7]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12][CH2:11]2)=[O:8])=[C:5]([O:19][CH3:20])[CH:4]=1
Reactant: CCOC(=O)CBr
Reactant: COc1cc(N)c(Cl)cc1C(=O)NC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCC(NC(=O)c2cc(Cl)c(N)cc2OC)CC1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
A mixture of-3.20 g of 4-amino-5-chloro-2-methoxy-N-(4-piperidinyl)benzamide hydrochloride, 1.22 ml of ethyl bromoacetate, 3.04 g of porassium carbonate, and 32 ml of N,N-dimethylformamide was stirred for 2.5 hours with heating at 60° C. The reaction mixture was concentrated under reduced pressure, and then the residue was added with water and extracted with dichloromethane. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give brown oil. The result was converted to the hydrochloride by an ordinary method to afford 3.31 g of pale yellow crystals. Recrystallization from ethanol gave colorless plates, m.p. 196.5°-198.5° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:31]([Cl:34])=[CH:32][N:33]=1)[C:5]([NH:7][C:8]1[CH:30]=[CH:29][C:11]2[CH2:12][CH2:13][C:14]3[C:15]([C:26]([NH2:28])=[O:27])=[N:16][N:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[C:18]=3[C:10]=2[CH:9]=1)=[O:6].[NH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>CCO>[Cl:34][C:31]1[C:4]([C:5]([NH:7][C:8]2[CH:30]=[CH:29][C:11]3[CH2:12][CH2:13][C:14]4[C:15]([C:26]([NH2:28])=[O:27])=[N:16][N:17]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=5)[C:18]=4[C:10]=3[CH:9]=2)=[O:6])=[CH:3][C:2]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[N:33][CH:32]=1
Reactant: C1CNCCN1
Reactant: NC(=O)c1nn(-c2ccc(F)cc2)c2c1CCc1ccc(NC(=O)c3cc(Cl)ncc3Cl)cc1-2
Solvent: CCO
Product: NC(=O)c1nn(-c2ccc(F)cc2)c2c1CCc1ccc(NC(=O)c3cc(N4CCNCC4)ncc3Cl)cc1-2
Reaction time: 24 h
Yield: 53 %

Procedure:
The title compound was synthesized by the same procedure as in Example 214 starting with the title compound of Example 248 (1 g, 0.0020 mol) and piperazine (3.44 g, 0.040 mol) in 5 mL of EtOH. The reaction was run at 100° C. for 24 h. The off-white precipitate that formed in the crude reaction mixture was filtered and washed with EtOH to afford 0.579 g of title compound (yield: 53%). 1H NMR (300 MHz, d6-DMSO): 2.67 (t, 4H, J=4.9 Hz), 2.85-2.90 (m, 4H), 3.36 (t, 4H, J=4.9 Hz), 6.80 (s, 1H), 7.18-7.19 (m, 1H), 7.25 (s, 1H), 7.27-7.35 (m, 3H), 7.37-7.39 (dd, 1H, J=8 Hz, 2 Hz), 7.51-7.55 (m, 3H), 8.09 (s, 1H), 10.28 (s, 1H). M=1=547
Reaction SMILES: [CH:1]1([C:6]2[CH:31]=[CH:30][C:9]([CH2:10][O:11][C:12]3[CH:13]=[CH:14][C:15]4[N:19]5[CH2:20][CH2:21][CH:22]([CH2:23][C:24]([O:26]CC)=[O:25])[C:18]5=[N:17][C:16]=4[CH:29]=3)=[CH:8][C:7]=2[C:32]([F:35])([F:34])[F:33])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+].Cl>O1CCOCC1>[CH:1]1([C:6]2[CH:31]=[CH:30][C:9]([CH2:10][O:11][C:12]3[CH:13]=[CH:14][C:15]4[N:19]5[CH2:20][CH2:21][CH:22]([CH2:23][C:24]([OH:26])=[O:25])[C:18]5=[N:17][C:16]=4[CH:29]=3)=[CH:8][C:7]=2[C:32]([F:34])([F:35])[F:33])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CC1CCn2c1nc1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CC1CCn2c1nc1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.3 %

Procedure:
Ethyl 2-(6-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-yl)acetate (0.109 g, 0.224 mmol) was dissolved in dioxane (2.5 mL) and 1.0 M aqueous lithium hydroxide (0.672 mL, 0.672 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 h and then acidified (pH 2) with 1.0 M HCl. The reaction mixture was extracted three times with EtOAc and the combined extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound (103 mg). LCMS m/z=459.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54-1.65 (m, 2H), 1.67-1.79 (m, 2H), 1.80-1.91 (m, 2H), 2.05-2.14 (m, 2H), 2.42-2.53 (m, 1H), 2.89 (d, J=7.1 Hz, 1H), 2.95-3.22 (m, 2H), 3.33-3.43 (m, 1H), 3.78-3.87 (m, 1H), 4.03-4.12 (m, 1H), 4.14-4.23 (m, 1H), 5.09 (s, 2H), 6.88 (d, J=2.4 Hz, 1H), 6.97 (dd, J=8.8, 2.5 Hz, 1H), 7.48 (d, J=8.2 Hz, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.62 (d, J=8.8 Hz, 1H), 7.68 (s, 1H).
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[C:16]1[N:23]=[C:24]([CH:26]2[CH2:30][O:29]C(C)(C)[O:27]2)[O:25][C:15]1=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[C:16]1[N:23]=[C:24]([CH:26]([OH:27])[CH2:30][OH:29])[O:25][C:15]1=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2]
Reactant: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc4oc(C5COC(C)(C)O5)nc4c3c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc4oc(C(O)CO)nc4c3c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.6 %

Procedure:
A solution of 200 mg of 2-(2,2-dimethyl-1,3-dioxolan-4-yl)-10-methoxymethyl-oxazolo-[4,5-g]-β-carboline-9-carboxylic acid isopropyl ester in 20 ml of methylene chloride is mixed drop by drop at room temperature with 1 ml of trifluoroacetic acid, and it is stirred at room temperature under protective gas for another 4 hours. The reaction solution is neutralized with the equimolar amount of sodium bicarbonate solution. The precipitated solid product is suctioned off and washed with methylene chloride. After the drying in a vacuum at 50° C., 112 mg of 2-(1,2-dihydroxyethyl)-10-methoxymethyl-oxazolo-[4,5-g]-β-carboline-9-carboxylic acid isopropyl ester with a melting point of 168° C. (decomposition) is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.[C:15]([CH2:17][C:18]([NH2:20])=[O:19])#[N:16].[H-].[Na+].Cl.O1CCOCC1>C1COCC1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH:17]([C:18](=[O:19])[NH2:20])[C:15]#[N:16])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: N#CCC(N)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C(C#N)C(N)=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 68 %

Procedure:
Starting material 25 (10 g, 50 mmol) and cyanacetamide (26, 8.4 g, 100 mmol) were dissolved in dry THF and NaH (60% ig, 4 g, 100 mmol) was added. The reaction was stirred over night at ambient temperature. Now it was cooled to 0° C. and 4 N HCl/Dioxan was added. The reaction mixture was concentrated in vacuo, the solid residue crystallized with 400 ml isopropyl ethyl ether, resulting crystals were filtered and dried. Then the crystals were washed with water and again filtered and dried. Thereby 8.9 g of the desired product 27 (67%, 34 mmol) were isolated.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:25][N:26]1[C:30]2[CH:31]=[C:32]([C:35]([OH:37])=O)[CH:33]=[CH:34][C:29]=2[N:28]=[N:27]1.CN(C=O)C.[F:43][C:44]([F:72])([C:68]([F:71])([F:70])[F:69])[CH2:45][O:46][C:47](=[O:67])[C@H:48]([OH:66])[CH2:49][C@H:50]([NH2:65])[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([Cl:64])[CH:59]=2)=[CH:54][CH:53]=1.CCN(C(C)C)C(C)C>>[F:72][C:44]([F:43])([C:68]([F:69])([F:70])[F:71])[CH2:45][O:46][C:47](=[O:67])[C@H:48]([OH:66])[CH2:49][C@H:50]([NH:65][C:35]([C:32]1[CH:33]=[CH:34][C:29]2[N:28]=[N:27][N:26]([OH:25])[C:30]=2[CH:31]=1)=[O:37])[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([Cl:64])[CH:59]=2)=[CH:54][CH:53]=1
Reactant: O=C(O)c1ccc2nnn(O)c2c1
Reactant: N[C@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C[C@@H](O)C(=O)OCC(F)(F)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C[C@@H](O)C(=O)OCC(F)(F)C(F)(F)F)c1ccc2nnn(O)c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 7.1 %

Procedure:
HATU (37.9 mg, 99.6 μmol) was added to a solution of 1-hydroxy-1H-1,2,3-benzotriazole-6-carboxylic acid (14.9 mg, 83 μmol) in DMF (0.5 mL, 6.4 mmol) and the resulting mixture was stirred at room temperature for 5 minutes. (2R,4R)-4-Amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid 2,2,3,3,3-pentafluoropropyl ester (30.0 mg, 66.4 μmol) was added to the mixture, followed by DIPEA (35 μL, 0.2 mmol) dropwise over 5 minutes, and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo to yield a yellow liquid, which was purified by preparative HPLC to yield the title compound as a white solid (2.9 mg, purity 100%). MS m/z [M+H]+ calc'd for C27H22ClF5N4O5, 613.12. found 613.0.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:18](Cl)(=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[C:18]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: CCCCCC(=O)Cl
Product: CCCCCC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Yield: 83 %

Procedure:
Beginning with 0.01 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.0077 mL (0.048 mMol) hexanoyl chloride, 0.012 gm (84%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: [O:1]1[CH:6]([C:7]([OH:9])=O)[CH2:5][O:4][C:3]2[CH:10]=[CH:11][CH:12]=[CH:13][C:2]1=2.[NH2:14][C:15]1[CH:16]=[CH:17][C:18]2[O:22][C:21]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[N:20][C:19]=2[CH:29]=1>>[N:26]1[CH:25]=[CH:24][C:23]([C:21]2[O:22][C:18]3[CH:17]=[CH:16][C:15]([NH:14][C:7]([CH:6]4[O:1][C:2]5[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=5[O:4][CH2:5]4)=[O:9])=[CH:29][C:19]=3[N:20]=2)=[CH:28][CH:27]=1
Reactant: Nc1ccc2oc(-c3ccncc3)nc2c1
Reactant: O=C(O)C1COc2ccccc2O1
Product: O=C(Nc1ccc2oc(-c3ccncc3)nc2c1)C1COc2ccccc2O1

Procedure:
The general procedure for compound 8 was followed using starting materials 2,3-dihydrobenzo [b][1,4]dioxine-2-carboxylic acid and compound 4 (5-thiazole) to give title compound Q20 (73%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 4.31 (dd, J, =11.6 Hz, J2=7.2 Hz, 1H), 4.66 (dd, J1=12 Hz, J2=2.8 Hz, 1H), 4.86 (dd, J, =7.4 Hz, J2=2.8 Hz, 1H), 6.93-6.96 (m, 3H), 7.06-7.08 (m, 1H), 7.59 (s, 2H), 8.07-8.08 (m, 2H), 8.14 (s, 1H), 8.43 (s, 1H), 8.83 (d, J=5.6 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 65.5, 73.5, 111.2, 112.6, 117.3, 118.0, 119.6, 121.2, 122.3, 123.0, 134.2, 134.3, 141.5, 142.4, 143.4, 148.2, 150.9, 161.9, 165.4; ESI-HRMS for C21H16N3O4(M+H)+ calcd. 374.1141. found 374.1138.
Reaction SMILES: CC(C1C(S(C)=O)=C(N)N([C:13]2[C:18](Cl)=[CH:17][C:16]([C:20](F)(F)F)=[CH:15][C:14]=2Cl)N=1)=O.CC[S+]([O-])[C:28]1[C:29](C#N)=[N:30][N:31](C2C(Cl)=CC(C(F)(F)F)=CC=2Cl)C=1N.C1C(C(F)(F)F)=CC(Cl)=C(N2N=C(C#N)C([S+]([O-])C(F)(F)F)=C2N)C=1Cl.COC1C(=O)C=C/C(=C\NC2N(C3C(Cl)=CC(C(F)(F)F)=CC=3Cl)N=C(C#N)C=2SC(F)(F)F)/C=1.C1C=C(CNC2N(C3C(Cl)=CC(C(F)(F)F)=CC=3Cl)N=C(C#N)C=2SC(F)F)N=CC=1.C1N=CC(CNC2N(C3C(Cl)=CC(C(F)(F)F)=CC=3Cl)N=C(C#N)C=2SCF)=NC=1>>[C:16]1([C:20]2[CH:28]=[CH:29][NH:30][N:31]=2)[CH:15]=[CH:14][CH:13]=[CH:18][CH:17]=1
Reactant: CC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Reactant: CC[S+]([O-])c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: COC1=C/C(=C/Nc2c(SC(F)(F)F)c(C#N)nn2-c2c(Cl)cc(C(F)(F)F)cc2Cl)C=CC1=O
Agent: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1[S+]([O-])C(F)(F)F
Agent: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(NCc2ccccn2)c1SC(F)F
Product: c1ccc(-c2cc[nH]n2)cc1

Procedure:
acetoprole, ethiprole, fipronil, vaniliprole, pyriprole, and pyrafluprole.
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]([C:7]([NH:9][C@H:10]([CH3:15])[C:11]([F:14])([F:13])[F:12])=[O:8])=[C:5]([F:18])[CH:4]=1)#[N:2]>C(O)C.O.C(O)(=O)C.[Pd]>[NH2:2][CH2:1][C:3]1[CH:17]=[CH:16][C:6]([C:7]([NH:9][C@H:10]([CH3:15])[C:11]([F:12])([F:13])[F:14])=[O:8])=[C:5]([F:18])[CH:4]=1
Reactant: C[C@@H](NC(=O)c1ccc(C#N)cc1F)C(F)(F)F
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: C[C@@H](NC(=O)c1ccc(CN)cc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
Combine a solution of (R)-4-cyano-2-fluoro-N-(2,2,2-trifluoro-1-methyl-ethyl)-benzamide (0.904 g, 3.475 mmol) in absolute ethanol (26 mL), water (9.7 mL) and glacial acetic acid (1.2 mL) with 10% Pd/C (Degussa type E101, 0.27 g, 0.13 mmol) under nitrogen. Purge the mixture with nitrogen and then with hydrogen. Stir the slurry at room temperature under hydrogen at 55 psi for 30 min. Purge the reaction mixture with nitrogen and then filter the slurry over Celite®. Wash the filter cake with ethanol (100 mL) and THF (100 mL). Concentrate the filtrate and purify by SCX chromatography eluting with dichloromethane/methanol (1:1) to remove impurities and then with dichloromethane/2M ammonia in methanol (1:1) to elute product. Concentrate to afford the title compound as a colorless oil (0.86 g, 94%).