Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:11]3=[N:12][C:13](S(C)=O)=[N:14][CH:15]=[C:10]3[CH2:9][NH:8][C:7]2=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1.CS(C)=O>C(OCC)(=O)C>[CH:1]1([N:6]2[C:11]3=[N:12][C:13]([NH:28][C:25]4[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=4)=[N:14][CH:15]=[C:10]3[CH2:9][NH:8][C:7]2=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(N)cc1
Reactant: CS(=O)c1ncc2c(n1)N(C1CCCC1)C(=O)NC2
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(Nc2ncc3c(n2)N(C2CCCC2)C(=O)NC3)cc1
Reaction time: 3 h
Yield: 24.2 %

Procedure:
A solution of 300 mg (1.07 mmol) of 1-cyclopentyl-7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one, 527 mg (4.28 mmol) of p-anisidine, and 1.5 mL of dimethyl sulfoxide is heated at 130° C. for 30 hours, then cooled and diluted with ethyl acetate. The mixture is washed three times with aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated. The residual solids are washed with 9:1:0.1:0.1 chloroform/ethyl acetate/ethanol/triethylamine then with chloroform, and suspended in 150 mL of 7:3 chloroform/methanol. The suspension is diluted with 20 mL of hexane, stirred for 3 hours, and filtered to afford 88 mg (24%) of the title compound as an off-white powder: mp 247-249° C. (dec).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[S:16][C:15]([C:18]([NH:20][C@@H:21]4[CH:26]5[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]5)[CH2:22]4)=[O:19])=[CH:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[C:29]([Cl:34])(=[O:33])[CH:30]([CH3:32])[CH3:31]>>[ClH:34].[N:23]12[CH2:24][CH2:25][CH:26]([CH2:27][CH2:28]1)[C@@H:21]([NH:20][C:18]([C:15]1[S:16][C:17]3[C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([NH:2][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:4]=4)=[CH:10][CH:11]=[CH:12][C:13]=3[CH:14]=1)=[O:19])[CH2:22]2
Reactant: CC(C)C(=O)Cl
Reactant: Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1

Procedure:
50 mg (0.12 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide hydrochloride (Example 21) and 25.7 mg (0.24 mmol) of isobutyryl chloride are reacted together by general method F. 35.1 mg (64.9% of theory) of the title compound are obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:16]1([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])=[CH:25][CH:24]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.O>C(#N)C>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([N:19]2[CH2:18][CH2:17][N:16]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])=[CH:27][CH:28]=3)[CH2:21][CH2:20]2)[N:3]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: CC(=O)NCc1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(=O)NCc1ccc(CN2CCN(c3nc(Cl)cc(Cl)n3)CC2)cc1
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
To a solution of 2,4,6-trichloropyrimidine (1.0 g) and potassium carbonate (0.84 g) in acetonitrile (20 ml) was added a solution of N-(4-((piperazin-1-yl)methyl)phenylmethyl)acetamide (1.0 g) obtained in Example 78(2) in acetonitrile (20 ml) under ice-cooling over 5 min. The mixture was stirred at the same temperature for 30 min. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a pale-brown oil (1.6g). The obtained pale-brown oil was purified by silica gel column chromatography (developing solvent; chloroform:methanol=50:1) to give a crude purification product (0.28 g) of N-(4-((4-(4,6-dichloropyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide and a crude purification product (0.9 g) of N-(4-((4-(2,6-dichloropyriinidin-4-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide. The crude purification product of N-(4-((4-(4,6-dichloropyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide was crystallized from ethyl acetate:hexane to give the title compound (0.2 g) as white crystals, m.p.=139-140° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:16]=[CH:15][C:9]2[NH:10][C:11](=[O:14])[CH2:12][O:13][C:8]=2[CH:7]=1)=[O:4].[CH2:17]([O:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)C>[CH2:17]([O:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:2][C:3]([NH:5][C:6]2[CH:16]=[CH:15][C:9]3[NH:10][C:11](=[O:14])[CH2:12][O:13][C:8]=3[CH:7]=2)=[O:4])[CH2:27][CH2:26]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1ccc(COC2CCNCC2)cc1
Reactant: O=C(CCl)Nc1ccc2c(c1)OCC(=O)N2
Solvent: CCOCC
Product: O=C(CN1CCC(OCc2ccccc2)CC1)Nc1ccc2c(c1)OCC(=O)N2

Procedure:
The title compound is prepared from 2-chloro-N-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-acetamide (Example 153a) and 4-benzyloxy-piperidine according to the method described in Example 142b. Melting Point: 238-240° C. (diethylether)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:22](=[O:25])(=[O:24])[NH2:23])[C:12]=1[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])[C:7]([OH:9])=[O:8])([O-])=O.[H][H].[OH-].[Na+]>O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:22](=[O:24])(=[O:25])[NH2:23])[C:12]=1[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:14])=[O:15])[C:7]([OH:9])=[O:8]
Reactant: [H][H]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1S(=O)(=O)c1ccccc1

Procedure:
A suspension of 3-nitro-4-phenylsulphonyl-5-sulphamyl-benzoic acid (6 g) in water (300 ml) was hydrogenated at room temperature and 1.1 atmospheres hydrogen pressure after addition of Pd-on-carbon catalyst (0.3 g catalyst containing 10% Pd). After the hydrogen uptake had become negligible, the reaction mixture was neutralized by addition of 2N sodium hydroxide, and the catalyst was removed from the resulting suspension by filtration. The filtrate was adjusted to a pH of 2.5 by addition of 4N hydrochloric acid, and the precipitated 3-amino-4-phenylsulphonyl-5-sulphamyl-benzoic acid was collected by suction. After recrystallization from aqueous ethanol, the acid had a melting point of 278° C (decomp.).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].N1C=CC=CC=1.O[CH2:14][C:15]1[CH2:16][S:17][C@@H:18]2[CH:38]([NH:39]C(=O)CC3C=CC=CC=3)[C:37](=[O:49])[N:19]2[C:20]=1[C:21]([O:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].C(O)CCO>C(Cl)Cl>[NH2:39][CH:38]1[C:37](=[O:49])[N:19]2[C:20]([C:21]([O:23][CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])=[C:15]([CH2:14][Cl:2])[CH2:16][S:17][C@H:18]12
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: OCCCO
Solvent: c1ccncc1
Product: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 51 %

Procedure:
To a slurry of PCl5 (8.3 g, 40 mmoles) in CH2Cl2 (100 mL) was added pyridine (3.2 g, 40 mmoles) and the mixture was stirred for 20 minutes at 20° C. To the mixture was added benzhydryl 3-hydroxymethyl-7-phenylacetamido-3-cephem-4-carboxylate prepared in Preparation No. 3 (5.1 g, 10 mmoles) with stirring at -40° C., in one portion. The mixture was stirred at -10° C. for 15 minutes and allowed to stand at -10° C. to -15° C. for 7 hours. To the cooled solution (-20° C.) was added propane-1,3-diol (10 mL) and the mixture was allowed to stand at -20° C. for 16 hours and then at room temperature for 20 minutes with stirring. The resulting solution was washed with ice-water (2×20 mL) and saturated aqueous NaCl (10 mL), dried over MgSO4 and concentrated in vacuo. The gummy residue (12 g) was dissolved in a mixture of CHCl3 and n-hexane (2:1), and subjected to chromatography using a silica gel column (200 g) and the same solvent as eluant. Fractions containing the title compound were evaporated in vacuo and the residue triturated with n-hexane to give the title product (2.1 g, 51%), melting at >110° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1>ClC1C=CC=CC=1>[O:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([N:1]3[CH2:6][CH2:11][CH:2]([NH2:1])[CH2:3][CH2:4]3)[C:11]=2[O:10][CH2:9][CH2:8]1
Reactant: Nc1cccc2c1OCCO2
Solvent: Clc1ccccc1
Product: NC1CCN(c2cccc3c2OCCO3)CC1
Yield: 68.1 %

Procedure:
20 g (59.0 mmol) of the above compound are mixed with 8.9 g (58.9 mmol) of 5-amino-1,4-benzodioxane in 120 ml of chlorobenzene at room temperature, and the mixture is then heated at reflux overnight. It is allowed to cool the product is deposited on the walls of the three-necked flask. The chlorobenzene phase is decanted off, and then the residue is taken up in 50 ml of water then 200 ml of N hydrochloric acid, washed with ether (significant emulsion), rendered basic in the cold with concentrated sodium hydroxide solution and extracted 3 times with 200 ml of ethyl acetate each time. The combined organic phases are dried over magnesium sulphate, concentrated (15 g), then chromatographed on silica (eluant:dichloromethane/methanol/ammonium hydroxide, 95/5/0.5) to yield 4.7 g of the desired product (theory: 13.8 g) in the form of a paste.
Reaction SMILES: [CH2:1]([C:12]#[N:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH3:14][CH2:15][CH:16](N)[CH2:17][OH:18]>C(O)CCC.O.O.C([O-])(=O)C.[Cd+2].C([O-])(=O)C>[CH2:15]([CH:16]1[CH2:17][O:18][C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[N:13]1)[CH3:14]
Reactant: CCCCCCCCCCCC#N
Reactant: CCC(N)CO
Agent: CC(=O)[O-]
Agent: [Cd+2]
Solvent: CCCCO
Solvent: O
Product: CCCCCCCCCCCC1=NC(CC)CO1
Yield: 89.6 %

Procedure:
25 g (137.9 mmoles) of undecyl cyanide was treated with 15.2 ml (165 mmoles) of DL-2-amino-1-butanol in presence of 919 mg (3.54 mmoles) of cadmium acetate dihydrate in 1-butanol as outlined under Example 1. 31.31 g (89.6%) of product was obtained on distillation at 124°-125° C./1.2-1.4 mm Hg.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8](=[O:9])[C:6]1=[O:7])=[O:4].C1CCN2C(=NCCC2)CC1.[NH2:27][C:28]([NH2:30])=[O:29]>O1CCCC1>[CH3:1][N:2]1[C:8]([OH:9])([C:6]([NH:27][C:28]([NH2:30])=[O:29])=[O:7])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:5][C:3]1=[O:4]
Reactant: CNC(=O)N1C(=O)C(=O)c2ccccc21
Reactant: NC(N)=O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CN1C(=O)Nc2ccccc2C1(O)C(=O)NC(N)=O

Procedure:
1-Methylcarbamoylisatin (10.2 g) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.3 g) are dissolved in tetrahydrofuran (100 ml), and thereto is added urea (4.5 g), and the mixture is refluxed for 10 hours. After cooling, the precipitates are taken by filtration, washed with water and methanol and recrystallized from a mixture of dimethylsulfoxide and ethanol to give 3-methyl-4-hydroxy-4-ureidocarbonyl-2-oxo-1,2,3,4-tetrahydroquinazoline, M.p.>280° C.,
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:23][C:24]2[CH:25]=[N:26][C:27]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[F:42])=[CH:28][C:29]=2[C:30]2[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=2)=[CH:18][C:17]=1[F:43])(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)(C)(C)C.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>ClCCl>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[Cl:22][C:20]1[C:19]([O:23][C:24]2[CH:25]=[N:26][C:27]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[F:42])=[CH:28][C:29]=2[C:30]2[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=2)=[CH:18][C:17]([F:43])=[C:16]([S:13]([NH:7][C:8]2[N:9]=[CH:10][S:11][CH:12]=2)(=[O:14])=[O:15])[CH:21]=1
Reactant: Cn1cc(-c2cc(-c3ccccc3F)ncc2Oc2cc(F)c(S(=O)(=O)N(C(=O)OC(C)(C)C)c3cscn3)cc2Cl)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2cc(-c3ccccc3F)ncc2Oc2cc(F)c(S(=O)(=O)Nc3cscn3)cc2Cl)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 35 %

Procedure:
20 mg (0.03 mmol) of tert-butyl((5-chloro-2-fluoro-4-((6-(2-fluorophenyl)-4-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)oxy)phenyl)sulfonyl)(thiazol-4-yl)carbamate was dissolved in 3 mL of dichloromethane, and 30 uL of trifluoroacetic acid was added thereto, followed by stirring at room temperature for 5 hours. After completion of the reaction as checked by TLC, the solvent was removed to obtain 7.0 mg (35% yield) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)=[O:11])[CH2:5]1.[O:22]=[C:23]1[NH:27][CH:26]=[C:25]([C:28](O)=[O:29])[O:24]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CN(C=O)C>[O:22]=[C:23]1[NH:27][CH:26]=[C:25]([C:28]([NH:1][CH2:2][CH2:3][CH:4]2[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=3)=[O:11])[CH2:5]2)=[O:29])[O:24]1
Reactant: O=C(O)c1c[nH]c(=O)o1
Reactant: NCCC1CN(C(=O)OCc2cc(Cl)cc(Cl)c2)CCO1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCC1CN(C(=O)OCc2cc(Cl)cc(Cl)c2)CCO1)c1c[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture comprising of 3,5-dichlorobenzyl 2-(2-aminoethyl)morpholine-4-carboxylate (Example 11, step 2) (178 mg, 0.534 mmol), 2-oxo-2,3-dihydrooxazole-5-carboxylic acid (Example 21, step 1) (68.9 mg, 0.534 mmol), T3P® (50% in DMF) (510 mg, 0.801 mmol), Huenig's base (466 μl, 2.67 mmol) in DMF (1781 μl) was stirred at room temperature. Another 1 equivalent of 2-oxo-2,3-dihydrooxazole-5-carboxylic acid was added and the reaction mixture was left stirring at room temperature overnight. The resulting reaction mixture was concentrated under reduced pressure and the crude product was diluted with EtOAc. The organic portion was dried with MgSO4, filtered and concentrated under reduced pressure. The crude material was dried loaded using silica onto an ISCO 4 g column eluting with 0-100% EtOAc (1% acetic acid) in iso-hexane. The product fractions were concentrated under reduced pressure to afford the title compound;
Reaction SMILES: [OH:1]O.[C:3]([S:7][C:8]1[C:9](=[O:16])[O:10][C:11]([CH3:15])=[CH:12][C:13]=1[OH:14])([CH3:6])([CH3:5])[CH3:4]>C(O)(=O)C>[C:3]([S:7]([C:8]1[C:9](=[O:16])[O:10][C:11]([CH3:15])=[CH:12][C:13]=1[OH:14])=[O:1])([CH3:6])([CH3:4])[CH3:5]
Reactant: Cc1cc(O)c(SC(C)(C)C)c(=O)o1
Reactant: OO
Solvent: CC(=O)O
Product: Cc1cc(O)c(S(=O)C(C)(C)C)c(=O)o1
Temperature: 0 °C
Reaction time: 66 h

Procedure:
Hydrogen peroxide (30%, 5.29 g., 0.467 mole) was added in one portion to a solution of 10.0 g. (0.0467 mole) of 3-tert.-butylthio-4-hydroxy-6-methyl-2-pyrone in 85 ml. of glacial acetic acid. The solution was allowed to stand at room temperature for 66 hours and then was poured into ice water, resulting in the precipitation of the pure product as 8.9 g. (83 percent) of white crystals, m.p. 119°C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:22])[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=[N:3]1.[F:23][C:24]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27].C(N(CC)CC)C>C1COCC1>[F:23][C:24]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:25]=1[C:26]([NH:22][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:8]=1)=[O:27]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CCOCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1nccc1-c1cc(NC(=O)c2ccc(F)cc2F)ccc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.9 %

Procedure:
A mixture of 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine (200 mg, 0.66 mmole), 2,4-difluoro-benzoyl chloride (140 mg, 1.2 eq), and triethylamine (0.2 mL, 2 eq) in 3 mL THF was stirred at room temperature for 10 minutes. The mixture was purified by HPLC to give title compound as a white solid (99 mg, 34%). 1H NMR (Acetone-d6, 400 MHz) δ 2.92-3.06 (m, 2H), 3.13-3.17 (i, 2H), 3.50-3.58 (m, 4H), 3.68 (s, 3H), 3.82-3.85 (m, 2H), 4.36 (t, 2M), 6.29 (s, 1H), 7.24 (d, J=9.09 Hz, 2H), 7.44 (dt, J=10.1, 2.78 Hz, 1H), 7.49 (s, 1H), 7.67 (s, 1H), 7.72-7.79 (m, 1H), 7.81 (dd, J=9.09, 2.78 Hz, 1H). Exact mass calculated for C23H24F2N4O3 442.2. found 443.5 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[NH2:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:24][C:22]1[CH:23]=[C:19]([NH:18][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:3]=2)[NH:20][N:21]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: Clc1nc(-c2ccccc2)cc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(-c3ccccc3)cc3ccccc23)[nH]n1

Procedure:
To a solution of 1-chloro-3-phenylisoquinoline (J. Het. Chem., 20, 1983, 121–128) (0.33 g, 1.37 mmol) in DMF (anhydrous, 5 mL) was added 3-amino-5-methylpyrazole (0.27 g, 2.74 mmol) and potassium carbonate (0.57 g, 4.13 mmol) and the resulting mixture was heated at reflux for 6 hours. The reaction mixture was then cooled and solvent removed in vacuo. The residue was extracted twice with ethyl acetate and the combined organic layers washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, gradient DCM-MeOH) to afford V-1 as a colourless oil; 1H NMR (MeOD) δ 2.23 (3H, s), 5.61 (1H, s), 7.41 (1H, m), 7.52(2H, m), 7.62(1H, m), 7.81(1H, m), 8.07(1H, d), 8.19(2H, m), 8.29(1H, s), 8.54 (1H, d); MS 301.2 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][C:16]([Cl:17])=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[Cl:17][C:16]1[N:15]=[C:14]([CH2:18][CH3:19])[N:11]2[CH2:12][CH2:13][NH:8][CH:9]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:24][CH:23]=3)[C:10]=12
Reactant: CCc1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCc1nc(Cl)c2n1CCNC2CCc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To an ice-cooled solution of 1-chloro-3-ethyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (226 mg; 0.494 mmol) in DCM (5 ml) was added 4N HCl in dioxane (2.5 ml; 10 mmol; 20 eq.). The resulting suspension was further stirred at 0° C. for 10 min., and at rt for 2 h. The volatiles were removed under vacuum and the resulting pale yellow chlorhydrate salt (240 mg) was purified by preparative HPLC in basic conditions leading to the pure product 1-chloro-3-ethyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine (89.6 mg; 51%). LC-MS: tR=0.77 min.; [M+H]+=358.36 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([P:8](=O)([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.II.C(P(CCCC)CCCC)CCC>C(#N)C.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([P:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: O=P(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: CCCCP(CCCC)CCCC
Agent: II
Solvent: C1CCOC1
Solvent: CC#N
Product: Clc1ccc(P(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.2 %

Procedure:
100 mg (0.262 mmol) of tris(4-chlorophenyl)phosphineoxide were treated with 6 mg I2 (26 μmol) and tributylphosphine 130 μL (0.52 mmol) in acetonitrile/THF (1:1 v/v) 1 mL. The mixture was stirred at room temperature for 10 minutes under nitrogen atmosphere before it was quenched with H2O (100 μL). The reaction mixture was diluted with ethyl acetate (10 mL) and was washed with portions of sat. NaHCO3 (3×5 mL). The organic fraction was dried with Na2SO4, filtered and the solvent evaporated under vacuum. The resulting residue was recrystallized from methanol (2 mL), the resulting crystals were filtered, washed and dried in vacuum, giving 95 mg (0.260 mmol, 99%) of tris(4-chlorophenyl)phosphine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24]C)=O)=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH2:26][CH3:27])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl-].[NH4+:29].N>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH2:29])=[O:24])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH2:26][CH3:27])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(Cc2ccc(CC(=O)OC)cc2)nc(-c2cccc(Cl)c2)n1
Reactant: [NH4+]
Agent: N
Agent: [Cl-]
Solvent: CO
Product: CCc1cc(Cc2ccc(CC(N)=O)cc2)nc(-c2cccc(Cl)c2)n1
Temperature: 100 °C
Reaction time: 43 h
Yield: 33.7 %

Procedure:
A 20-mL vial was charged with methyl 2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)acetate (113 mg, 0.30 mmol, 1.0 eq.) and ammonium chloride (48 mg, 0.89 mmol, 3.0 eq.). To this was added methanol (3 mL) followed by NH3 (7.5 mL, 7N in methanol, 53 mmol, 177 eq.). The vial was sealed and the resulting mixture was stirred at 100° C. for 43 hr. The crude reaction solution was adsorbed onto silica then purified by chromatography on silica gel using dichloromethane/methanol (0 to 5%) as eluent, followed by chromatography on silica gel using hexane/ethyl acetate (100:0 to 0:100) as eluent, to give 2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)acetamide (37 mg, 35% yield) as a white solid. MW=365.86. 1H NMR (DMSO-d6, 500 MHz) δ 8.38-8.33 (m, 2H), 7.61-7.53 (m, 2H), 7.41 (br s, 1H), 7.29 (d, J=8.0 Hz, 2H), 7.25 (s, 1H), 7.20 (d, J=8.0 Hz, 2H), 6.82 (br s, 1H), 4.09 (s, 2H), 3.32 (s, 2H), 2.77 (q, J=7.5 Hz, 2H), 1.26 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH3:1][CH:2]1[CH:11]=[C:10]2[CH:5]([CH:6]([CH2:13][CH2:14][CH:15]([OH:22])[CH2:16][CH:17]([OH:21])[CH2:18][CH2:19]O)[CH:7]([CH3:12])[CH:8]=[CH:9]2)[CH:4]([O:23][C:24](=[O:29])[CH:25]([CH3:28])[CH2:26][CH3:27])[CH2:3]1.CCN(C(C)C)C(C)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O>C(Cl)Cl>[OH:21][CH:17]1[CH2:18][CH2:19][O:22][CH:15]([CH2:14][CH2:13][CH:6]2[CH:5]3[C:10](=[CH:11][CH:2]([CH3:1])[CH2:3][CH:4]3[O:23][C:24](=[O:29])[CH:25]([CH3:28])[CH2:26][CH3:27])[CH:9]=[CH:8][CH:7]2[CH3:12])[CH2:16]1
Reactant: CCC(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCC(O)CC(O)CCO)C21
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCC3CC(O)CCO3)C21

Procedure:
To a cooled (−77° C.) solution of 73 mg (0.18 mmol) of 2-methyl-butyric acid 3,7-dimethyl-8-(3,5,7-trihydroxy-heptyl)-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl ester in 5 ml of methylene chloride is added 0.9 g (7 mmol) Hunig's base and 0.08 ml (0.5 mmol) triflic anhydride. After 30 minutes the reaction is quenched with saturated aqueous sodium bicarbonate. The phases are separated and the water phase is extracted twice with ethyl acetate. The organic phases are combined, washed with brine and dried over sodium sulfate. The solvent is evaporated and the crude product is purified by silica gel chromatography (diethyl ether/hexane 1/4) to afford the desired product as a colorless oil.