Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7])#[N:2].[ClH:13]>C1C=CC=CC=1.O.[Cd].ClC1C=CC=CC=1.ClC1C=CC=CC=1>[Cl:13][C:3]1[CH:4]=[CH:5][C:9]([C:6]([C:5]2[C:4]([CH3:12])=[C:3]([CH:11]=[CH:10][CH:9]=2)[C:1]#[N:2])=[O:7])=[CH:10][CH:11]=1
Reactant: Cc1c(C#N)cccc1C(=O)Cl
Reactant: Cl
Agent: [Cd]
Solvent: c1ccccc1
Solvent: O
Solvent: Clc1ccccc1
Product: Cc1c(C#N)cccc1C(=O)c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
The said benzene solution was cooled to 5° C. and then a solution of 27.4 g of 3-cyano-2-methyl-benzoyl chloride in 85 cc of benzene was added thereto. The mixture was allowed to return to room temperature and was stirred overnight. The mixture was refluxed for 31/2 hours and after cooling, the mixture was added to a solution of 30 cc of hydrochloric acid in 600 cc of water. The mixture was extracted with ether and the combined ether phases were washed successively with 1 N hydrochloric acid, water, 1 N sodium hydroxide and water until the wash waters were neutral. The organic phase was dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was empasted with 40 cc of petroleum ether, vacuum filtered, washed with petroleum ether and dried at room temperature under reduced pressure to obtain 30.6 g of 3-p-chlorobenzoyl-2-methyl-benzonitrile. For analysis, the product was crystallized from methanol and melted at 84° C. The compound occurred in the form of beige crystals soluble in methylene chloride and chloroform.
Reaction SMILES: O.O.O.[F-:4].[Al+3:5].[F-:6].[F-:7].O.O.O.[F-:11].[CH2:12]([N+:14]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH3:15])[CH3:13]>>[F:4][Al-:5]([F:11])([F:7])[F:6].[CH2:12]([N+:14]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH3:15])[CH3:13]
Reactant: [Al+3]
Reactant: [F-]
Agent: CC[N+](C)(CC)CC
Solvent: O
Product: F[Al-](F)(F)F
Reaction time: 0.5 h

Procedure:
6.90 g (50.0 mmol) of aluminum fluoride trihydrate was weighed and placed in a round flask made of PFA, and air in the flask was evacuated and then replaced by argon gas. While feeding argon gas to the flask through its inlet, 100 ml of dehydrated acetonitrile was added and the flask was sealed followed by stirring for 30 minutes. Then, while feeding argon gas similarly, 9.46 g (50.0 mmol) of triethylmethylammonium fluoride trihydrate was added portion wise, and the resultant mixture was further stirred for about 3 hours. The unreacted solid was filtered off, and then the solvent was distilled off to obtain about 9 g of white crude crystal of triethylmethylammonium tetrafluoroaluminate. This was subjected to recrystallization from 10 g of isopropanol. The amount of the product was 5.50 g, and the yield was 50% based on the charged raw material. Identification was made by elemental analysis and NMR, and a melting point was measured by TG-DTA.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:11]=[C:10]([CH:12]2[CH2:16][CH2:15][CH2:14][NH:13]2)[O:9][N:8]=1.[C:17]([O:21][C:22]([NH:24][C:25]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=NS(C(F)(F)F)(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[C:38]([O:37][C:35]([NH:34][C:25]([N:13]1[CH2:14][CH2:15][CH2:16][CH:12]1[C:10]1[O:9][N:8]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:11]=1)=[N:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])=[O:36])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)NC(=NS(=O)(=O)C(F)(F)F)NC(=O)OC(C)(C)C
Reactant: c1ccc(-c2cc(C3CCCN3)on2)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCCC1c1cc(-c2ccccn2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
2-[3-(Pyrid-2-yl)isoxazol-5-yl]pyrrolidine (Method 12) (1.5 g, 7 mmol) was added to a solution of N,N′-di(tertbutyloxycarbonyl)-N″-(trifluoromethylsulphonyl)guanidine (2.59 g, 6.6 mmol) and triethylamine (0.975 ml) in DCM and the mixture stirred at ambient temperature for 8 hours. The mixture was then washed with water, dried (MgSO4) and the volatiles removed by evaporation. The residue was purified by chromatography on silica gel eluting with DCM/methanol (100:0 increasing in polarity to 98:2) to give the title compound (2.3 g, 70%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][NH2:11])=[N:8][CH:9]=1)([O-:3])=[O:2].[NH:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH:17]=O.C(O)(=O)C>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][N:11]=[CH:17][C:13]2[NH:12][CH:16]=[CH:15][N:14]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NNc1ccc([N+](=O)[O-])cn1
Reactant: O=Cc1ncc[nH]1
Solvent: CC(=O)O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(NN=Cc2ncc[nH]2)nc1
Reaction time: 8 h

Procedure:
3.10 g (20.1 mmol) of 5-nitro-2-pyridylhydrazine and 2.00 g (20.8 mmol) of 2-imidazolecarbaldehyde were dissolved in 50 ml of ethanol. To this mixture, 1 ml of acetic acid was added and heated under reflux for 2 hours while being stirred. After the resultant reaction mixture was allowed to stand still overnight, coarse crystals precipitated were filtrated by the suction-filtration. The obtained coarse crystals were recrystallized from a hot ethanol solution to obtain a desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[CH:14]([C:17]1[CH:21]=[C:20]([NH:22][C:23]2[C:24]3[CH2:40][C:39]([CH3:42])([CH3:41])[CH2:38][C:25]=3[N:26]=[C:27]([N:29]3[CH2:33][CH2:32][CH2:31][C@H:30]3[C:34](OC)=[O:35])[N:28]=2)[NH:19][N:18]=1)([CH3:16])[CH3:15]>C1COCC1>[F:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:34]([C@@H:30]2[CH2:31][CH2:32][CH2:33][N:29]2[C:27]2[N:28]=[C:23]([NH:22][C:20]3[NH:19][N:18]=[C:17]([CH:14]([CH3:16])[CH3:15])[CH:21]=3)[C:24]3[CH2:40][C:39]([CH3:42])([CH3:41])[CH2:38][C:25]=3[N:26]=2)=[O:35])=[CH:3][CH:4]=1
Reactant: Nc1ccc(F)nc1
Reactant: COC(=O)[C@@H]1CCCN1c1nc2c(c(Nc3cc(C(C)C)n[nH]3)n1)CC(C)(C)C2
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)c1cc(Nc2nc(N3CCC[C@H]3C(=O)Nc3ccc(F)nc3)nc3c2CC(C)(C)C3)[nH]n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.9 %

Procedure:
To a stirred solution of 5-amino-2-fluoropyridine (79 mg, 0.703 mmol) in dry THF (2 mL) was added isopropyl magnesium chloride 2M in THF (0.43 mL, 0.86 mmol) dropwise under nitrogen atmosphere at 0° C. The resultant mixture was stirred at 0° C. for 30 min. To this was added a solution of (S)-methyl 1-(4-(3-isopropyl-1H-pyrazol-5-ylamino)-6,6-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylate (70 mg, 0.175 mmol) in THF (2 mL) dropwise at 0° C. and the reaction mixture was allowed to stir at RT for 2 h. The reaction mixture was cooled to 0° C. and quenched by saturated ammonium chloride solution (10 mL). The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×20 mL). The organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate. Removal of EtOAc under vacuum gave a crude oil which was purified by reverse phase HPLC to afford 15 mg of (S)—N-(6-fluoropyridin-3-yl)-1-(4-(3-isopropyl-1H-pyrazol-5-ylamino)-6,6-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide. 1H NMR (400 MHz, CD3OD, freebase) δ (ppm): 1.15-1.25 (m, 6H), 1.20 (s, 6H), 2.02-2.18 (m, 2H), 2.22-2.3.8 (m, 2H), 2.58 (s, 2H), 2.62 (s, 2H), 2.79-2.90 (m, 1H), 3.60-3.70 (m, 1H), 3.78-3.87 (m, 1H), 4.77 (dd, 1H), 6.25 (brs, 1H), 6.99 (dd, 1H), 7.97 (brs, 1H), 8.20 (s, 1H). The other enantiomer was obtained using the chiral (R) starting material.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:17][C:18]([OH:20])=O)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl:44][C:45]1[CH:51]=[CH:50][C:48]([NH2:49])=[CH:47][C:46]=1[CH:52]1[CH2:57][CH2:56][N:55]([CH3:58])[CH2:54][CH2:53]1>ClCCl>[Cl:44][C:45]1[CH:51]=[CH:50][C:48]([NH:49][C:18](=[O:20])[CH2:17][C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[CH:8][CH:9]=2)=[CH:47][C:46]=1[CH:52]1[CH2:53][CH2:54][N:55]([CH3:58])[CH2:56][CH2:57]1
Reactant: CN1CCC(c2cc(N)ccc2Cl)CC1
Reactant: O=C(O)Cc1ccc(-c2ccncc2)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CN1CCC(c2cc(NC(=O)Cc3ccc(-c4ccncc4)c4ccccc34)ccc2Cl)CC1
Reaction time: 0.5 h
Yield: 7.1 %

Procedure:
To a solution of 4 -(pyridin-4-yl)napth-1-ylacetic acid (D2, 260 mg, 1.0 mmol) in dichloromethane was added 1-hydroxybenzotriazole hydrate (153 mg, 1.0 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (200 mg, 1.0 mnmol) and the mixture stirred for 0.5 h. To the mixture was added dropwise a solution of 4-chloro-3-(1-methylpiperidin-4-yl)aniline (D7, 200 mg, 0.90 mmol) in dichloromethane (3 ml) and stirring continued for 48 h. Purification of the crude by flash chromatography gave the title compound as a white solid (30 mg, 7%).
Reaction SMILES: S1C=CN=C1CSCCN.[C:11]([CH:13]=[C:14](OC)OC)#[N:12].[C:19]([CH:21]=[C:22](OC)[NH:23][CH2:24][CH2:25][S:26][CH2:27][C:28]1[S:29][CH:30]=[CH:31][N:32]=1)#[N:20].C(N)C#C>>[C:19]([CH:21]=[C:22]([NH:12][CH2:11][C:13]#[CH:14])[NH:23][CH2:24][CH2:25][S:26][CH2:27][C:28]1[S:29][CH:30]=[CH:31][N:32]=1)#[N:20]
Reactant: COC(=CC#N)OC
Reactant: COC(=CC#N)NCCSCc1nccs1
Agent: C#CCN
Agent: NCCSCc1nccs1
Product: C#CCNC(=CC#N)NCCSCc1nccs1

Procedure:
When 2-[(thiazol-2-yl)methylthio]ethylamine is reacted with 1-cyano-2,2-bis(methoxy)ethylene [prepared according to the procedure described in J. Chem. Soc., (Suppl. Issue No. 1), S106-111 (1949)] and the resultant 1-cyano-2-methoxy-2-{2-[(thiazol-2-yl)methylthio]ethylamino}ethylene is reacted with propargylamine in the procedure of Example 1, the title compound is produced.
Reaction SMILES: C([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][C@@H:13]([C:15](=[O:21])[NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:12][CH2:11][C@@H:10]1[NH:22][C:23]([C:25]1[NH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([Cl:34])=[CH:29][CH:28]=2)=[O:24])=O)(C)(C)C.Cl.[CH3:36][N:37]1[CH2:42][CH2:41][C:40]2[N:43]=[C:44](C([O-])=O)[S:45][C:39]=2[CH2:38]1.[Li+]>O1CCOCC1>[ClH:34].[C:17]([NH:16][C:15]([C@H:13]1[CH2:12][CH2:11][C@H:10]([NH:22][C:23]([C:25]2[NH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([Cl:34])=[CH:29][CH:28]=3)=[O:24])[C@H:9]([NH:8][C:6]([C:44]2[S:45][C:39]3[CH2:38][N:37]([CH3:36])[CH2:42][CH2:41][C:40]=3[N:43]=2)=[O:5])[CH2:14]1)=[O:21])([CH3:18])([CH3:20])[CH3:19]
Reactant: CN1CCc2nc(C(=O)[O-])sc2C1
Reactant: CC(C)(C)NC(=O)[C@H]1CC[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Li+]
Solvent: C1COCCO1
Product: CN1CCc2nc(C(=O)N[C@@H]3C[C@@H](C(=O)NC(C)(C)C)CC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1

Procedure:
(1S,2R,4S)-N2-(tert-Butoxycarbonyl)-4-[N-(tert-butyl)carbamoyl]-N1-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine was treated with a 4N dioxane solution of hydrochloric acid and then condensed with lithium 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate in a similar manner to Example 118 to obtain the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH2:26]([O:33][C:34]1[CH:35]=[CH:36][C:37]([CH3:43])=[C:38]([CH:42]=1)[C:39](Cl)=[O:40])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([O:33][C:34]1[CH:35]=[CH:36][C:37]([CH3:43])=[C:38]([C:39]([N:20]2[CH2:21][CH2:22][CH:17]([N:15]3[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]4[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=4)=[N:16]3)[CH2:18][CH2:19]2)=[O:40])[CH:42]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: Cc1ccc(OCc2ccccc2)cc1C(=O)Cl
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(OCc5ccccc5)ccc4C)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 5-(benzyloxy)-2-methylbenzoyl chloride (compound F2) as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl.[Cl:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:22])[CH:13]([CH2:18]N(C)C)[CH2:14][S:15]2)=[CH:10][CH:9]=1>O>[Cl:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:22])[CH:13]([CH2:18][C:2]3[NH:1][CH:5]=[CH:4][N:3]=3)[CH2:14][S:15]2)=[CH:10][CH:9]=1
Reactant: c1c[nH]cn1
Reactant: CN(C)CC1CSc2cc(Cl)ccc2C1=O
Agent: Cl
Solvent: O
Product: O=C1c2ccc(Cl)cc2SCC1Cc1ncc[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve imidazole (25.8 gms., 380 mmols) in water (100 ml.) and add 7-chloro-3-(dimethylaminomethyl)thiochroman-4-one hydrochloride (11.1 gms., 38.0 mmols). Stir the reaction mixture overnight at room temperature, then add water (1 liter) and extract with chloroform (500 ml.). Wash the chloroform solution with 2 liter portions of water, dry over anhydrous magnesium sulfate, filter and evaporate in vacuo to a residue. Chromatograph the residue on a silica gel column eluting with chloroform. Combine the like eluates as determined by thin layer chromatography and evaporate in vacuo to a residue comprising 7-chloro-3-(1'-imidazolylmethyl)thiochroman-4-one. Further purify by recrystallization from chloroform/hexane, m.p. 104°-105° C.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[O:8][C:9]1[CH:10]=[C:11]([C:17]2[CH:18]=[N:19][C:20](=[O:23])[NH:21][CH:22]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16].[H][H]>C(O)C.[Ni]>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[O:8][C:9]1[CH:10]=[C:11]([C:17]2[CH2:22][NH:21][C:20](=[O:23])[NH:19][CH:18]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1ccc(-c2cnc(=O)[nH]c2)cc1OC1CC2CCC1C2
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: COc1ccc(C2=CNC(=O)NC2)cc1OC1CC2CCC1C2
Yield: 31.3 %

Procedure:
The pyrimidinone (0.38 g, 1.22 mmol) is dissolved in 20 ml ethanol and treated with 0.5 g Raney Nickel, 40 psi hydrogen and refluxed for 18 hours. The reaction is cooled, filtered through celite, and the filtrate concentrated in vacuo. The residue is crystallized from ethyl acetate to afford 0.12 g (31.8%) of the dihydro pyrimidinone as a crystalline solid comprising a 7:3 mixture of endo/exo norbornyl isomers.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([Sn](C)(C)C)[N:11]=[N:10][N:9]=1.Cl>C1(C)C=CC=CC=1.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[N:10][N:9]=1
Reactant: C[Sn](C)(C)n1nnnc1-c1ccccc1Br
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Brc1ccccc1-c1nnn[nH]1
Reaction time: 0.08 h

Procedure:
To a solution of 1.0 g of 5-(2-bromophenyl)-1-(trimethylstannyl)-1H-tetrazole in toluene/THF (10:1) at room temperature is added HCl gas, via a bubbler. Gas addition is continued for 5 minutes after the appearance of a precipitate and the solid is then isolated by filtration and washed with hexanes.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([NH2:12])[C:4]=2[N:3]=1.[O:13]=[C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:23])[N:15]1[CH2:24][CH2:25][CH2:26][CH:27]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([NH:12][CH2:27][CH2:26][CH2:25][CH2:24][N:15]3[C:16](=[O:23])[C:17]4[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:14]3=[O:13])[C:4]=2[N:3]=1
Reactant: O=CCCCN1C(=O)c2ccccc2C1=O
Reactant: Cc1ccc2c(n1)C(N)CCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc2c(n1)C(NCCCCN1C(=O)c3ccccc3C1=O)CCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a solution of 2-methyl-5,6,7,8-tetrahydroquinolin-8-ylamine (237 mg, 1.46 mmol) in CH2Cl2 (20 mL) at room temperature under inert atmosphere was added 4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyraldehyde (159 mg, 0.731 mmol) followed by sodium triacetoxyborohydride (309 mg, 2.92 mmol). The reaction mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate solution (10 mL) was added and the mixture was extracted with dichloromethane (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated. The resultant material was purified by column chromatography on silica gel (10:1:0.5 CH2Cl2: MeOH: NH4OH) to provide the product as a yellow oil (210 mg, 79%): 1H NMR (CDCl3): δ 1.56-1.83 (m, 6H), 1.90-2.04 (m, 2H), 2.04-2.18 (m, 2H), 2.47 (s, 3H), 2.64-2.80 (m, 4H), 3.70-3.76 (m, 3H), 6.90 (d, 1H, J=7.8 Hz), 7.24 (d, 1H, J=7.8 Hz), 7.69-7.73 (m, 2H), 7.81-7.85 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=O)=[N:6][CH:7]=1.C1(P(=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C>[CH2:33]([O:32][C:30](=[O:31])[CH:29]=[CH:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)[CH3:34]
Reactant: O=Cc1ccc(Br)cn1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
5-Bromopyridine-2-carbaldehyde (502 mg, 2.70 mmol) was added to a solution of ethyl (triphenyl-λ5-phosphanylidene)acetate (1570 mg, 4.51 mmol) in DMF (5.00 mL) and the reaction mixture was stirred at room temperature for 40 minutes. The mixture was poured into ice-water, and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure. A mixture of hexane:ethyl acetate (2:1) was added to the crude residue and the insoluble materials were filtered off. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography (4% ethyl acetate in hexanes) to afford ethyl-3-(5-bromopyridin-2-yl)prop-2-enoate MS APCI calc'd for C10H11BrNO2 [M+H]+ 256 and 258. found 256 and 258.
Reaction SMILES: O1C=C(CN)N=C1.[F:8][C:9]([F:18])([F:17])[C:10]1[S:11][CH:12]=[C:13]([CH2:15][NH2:16])[N:14]=1.[F:19][C:20]1[CH:41]=[CH:40][C:23]([CH2:24][N:25]2[CH2:29][CH2:28][N:27]([C:30]3[CH:31]=[C:32]([CH:36]=[CH:37][N:38]=3)[C:33](O)=[O:34])[C:26]2=[O:39])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:24][N:25]2[CH2:29][CH2:28][N:27]([C:30]3[CH:31]=[C:32]([CH:36]=[CH:37][N:38]=3)[C:33]([NH:16][CH2:15][C:13]3[N:14]=[C:10]([C:9]([F:8])([F:17])[F:18])[S:11][CH:12]=3)=[O:34])[C:26]2=[O:39])=[CH:40][CH:41]=1
Reactant: O=C(O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Reactant: NCc1csc(C(F)(F)F)n1
Agent: NCc1cocn1
Product: O=C(NCc1csc(C(F)(F)F)n1)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Yield: 30 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace oxazol-4-ylmethanamine with (2-(trifluoromethyl)thiazol-4-yl)methanamine to react with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinic acid, 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-((2-(trifluoromethyl)thiazol-4-yl)methyl)isonicotinamide was obtained as a colorless solid in 30% yield: mp 66-68° C.; 1H NMR (300 MHz, CDCl3) δ 8.68 (s, 1H), 8.36 (d, J=5.1 Hz, 1H), 7.59 (s, 1H), 7.35 (d, J=5.1 Hz, 1H), 7.28-7.20 (m, 2H), 7.17-6.99 (m, 3H), 4.78 (d, J=6.0 Hz, 2H), 4.43 (s, 2H), 4.03 (t, J=8.0 Hz, 2H), 3.37 (t, J=8.0 Hz, 2H); MS (ES+) m/z 479.8 (M+1).
Reaction SMILES: [OH:1][C:2]12[CH2:16][CH:15]([CH3:17])[CH2:14][C:13](=[O:18])[CH:12]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2.C(N(CC)CC)C.[Si:26](OS(C(F)(F)F)(=O)=O)([CH3:29])([CH3:28])[CH3:27].[NH4+].[Cl-]>C1COCC1.C(OCC)C>[CH3:17][CH:15]1[CH2:16][C:2]2([O:1][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[C:13](=[O:18])[CH2:14]1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC1CC(=O)C2CCCCCCCCCC2(O)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1CC(=O)C2CCCCCCCCCC2(O[Si](C)(C)C)C1
Yield: 98.6 %

Procedure:
A mixture of 25 mg (0.1 mmol) of (16) and 17 μl (0.12 mmol) triethyl amine in 0.5 ml THF was treated at 0° C. with 21 μl (0.11 mmol) TMSOTf. After 30 min 8 μl (0.06 mmol) triethyl amine and 10 μl (0.055 mmol) TMSOTf were added. After 10 min the mixture was diluted with diethyl ether and was poured into 2 ml of a saturated NH4Cl solution. The organic phase was separated, diluted with 3 ml of dichloro methane and the solvent was evaporated at room temperature under vacuum to afford 32 mg (19) (yield: 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8][CH2:9][C:10]#[N:11])[CH:5]=[CH:4][C:3]=1[OH:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:24](N)[CH2:25][NH2:26].ClC1C=CC=CC=1Cl.Cl>C(O)(C)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([S:8][CH2:9][C:10]2[NH:26][CH2:25][CH2:24][N:11]=2)[CH:5]=[CH:4][C:3]=1[OH:12]
Reactant: N#CCSc1ccc(O)c(Cl)c1
Reactant: NCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: Clc1ccccc1Cl
Product: Oc1ccc(SCC2=NCCN2)cc1Cl
Reaction time: 1.5 h

Procedure:
A mixture of 19.95 g of 2-chloro-4-(cyanomethylthio)-phenol, 23.3 g of ethylenediamine p-toluenesulfonate and 75 ml of 1,2-dichlorobenzene was heated at 160°-175° C. with stirring under a small flow of nitrogen for 1.5 hours. After cooling the reaction mixture, the 1,2-dichlorobenzene was decanted off. The residue was slurried in water and CH2Cl2 and then basified. The CH2Cl2 layer was separated from the mixture and an insoluble gum obtained. The gum was put in solution in isopropyl alcohol, acidified with hydrochloric acid in isopropyl alcohol and then cooled. The crude product was removed by filtering and recrystallized from isopropyl alcohol. Recrystallized 2-chloro-4-(((2-imidazolin-2-yl)methyl)thio)-phenol hydrochloride was found to have a m.p. of 181°-183° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7]C)=O.[NH2:14][O:15][CH2:16][CH2:17][OH:18].C[O-].[Na+].Cl>CO.O>[Cl:1][C:2]1[C:3]([NH2:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([NH:14][O:15][CH2:16][CH2:17][OH:18])=[O:7]
Reactant: COC(=O)c1cc(Cl)cc(Cl)c1N
Reactant: NOCCO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1c(Cl)cc(Cl)cc1C(=O)NOCCO
Temperature: 50 °C
Reaction time: 8 h

Procedure:
9 g (40.9 mmol) of methyl 3,5-dichloro-2-aminobenzoate and 6.3 g (81.8 mmol) of 2-(aminooxy)ethanol are initially charged in 90 ml of methanol, and 22.1 g (122.7 mmol) of sodium methoxide as a 30% strength solution in methanol are added dropwise at 20° C. The mixture is stirred at 50° C. overnight. The mixture is cooled and poured onto 400 ml of water, and the pH is adjusted to 3 using 1 N hydrochloric acid. The mixture is extracted 3 times with in each case 150 ml of ethyl acetate and the extracts are dried with sodium sulphate and concentrated using a rotary evaporator.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[N:5]([CH3:20])[N:4]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][N:5]1[C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)=[CH:7][C:3]([CH2:2][N:21]2[CH2:26][CH2:25][N:24]([CH2:2][C:3]3[CH:7]=[C:6]([C:8]4[CH:9]=[C:10]([O:18][CH3:19])[C:11]([O:16][CH3:17])=[C:12]([O:14][CH3:15])[CH:13]=4)[N:5]([CH3:20])[N:4]=3)[CH2:23][CH2:22]2)=[N:4]1
Reactant: COc1cc(-c2cc(CCl)nn2C)cc(OC)c1OC
Reactant: C1CNCCN1
Product: COc1cc(-c2cc(CN3CCN(Cc4cc(-c5cc(OC)c(OC)c(OC)c5)n(C)n4)CC3)nn2C)cc(OC)c1OC

Procedure:
3-Chloromethyl-1-methyl-5-(3,4,5-trimethoxy-phenyl)pyrazole (119 mg) and piperazine (17 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.