Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-]C(C)C)C.[C:9]1([CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]#[N:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(Br)C.P([O-])([O-])([O-])=O>C1COCC1>[C:18]1([C:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)([CH2:2][CH3:3])[C:16]#[N:17])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)[N-]C(C)C
Reactant: N#CC(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCBr
Product: CCC(C#N)(c1ccccc1)c1ccccc1
Temperature: -30 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
173 ml (0.259 mol) of a 1.5 M solution of LDA in THF were added dropwise to a solution of 50.0 g (0.259 mol) of diphenylacetonitrile in 500 ml of THF (abs.) at −78° C. under argon, and the mixture was then stirred at −30° C. for one hour. Then, at −78° C., 28.23 g (0.259 mol) of ethyl bromide were added. The mixture was allowed to reach room temperature and was stirred for 16 hours. Subsequently, 80 ml of phosphate buffer (pH 7) were added and the mixture was evaporated. The residue was taken up in water and extracted three times with ethyl acetate. The combined organic phases were dried over MgSO4, and the solvent was stripped off under reduced pressure. The crude product was chromatographed on silica gel with n-heptane/acetic acid (20:1). 38.2 g (67%) of 2,2-diphenylbutyronitrile were obtained.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([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:4]1.[C:27](O)(=[O:31])[CH2:28][CH2:29][CH3:30]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([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:27](=[O:31])[CH2:28][CH2:29][CH3:30])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: CCCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: CCCC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, off-white solid (60 mg, 60%), MS (ISP) m/z=397.3 [(M+H)+], mp 155° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and butyric acid.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[C:30]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)(=[O:32])[CH3:31]>>[C:30]([N:33]1[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][O:4][C:5]2[C:13]3[C:8](=[N:9][CH:10]=[N:11][C:12]=3[NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[C:17]([Cl:29])[CH:16]=3)[NH:7][N:6]=2)[CH2:35][CH2:34]1)(=[O:32])[CH3:31]
Reactant: CC(=O)N1CCNCC1
Reactant: ClCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: CC(=O)N1CCN(CCOc2n[nH]c3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)CC1
Yield: 46 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and N-acetylpiperazine to give the title compound in 46% yield; NMR Spectrum: 1.96 (s, 3H), 2.44 (t, 2H), 2.50 (hidden by DSMO, 2H), 2.83 (t, 2H), 3.37-3.41 (m, 4H), 4.43 (t, 2H), 5.28 (s, 2H), 7.24 (d, 1H), 7.37 (t, 1H), 7.55-7.58 (m, 2H), 7.86-7.91 (m, 2H), 8.29 (s, 1H), 8.46 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 523 (MH+).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][C@H:8]2[C:18]([O:20][CH3:21])=[O:19])[C:3]1=[O:22].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[C:14]([NH:13][C@H:10]1[CH2:9][C@@H:8]([C:18]([O:20][CH3:21])=[O:19])[C@@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=3)[C:3]2=[O:22])[CH2:12][CH2:11]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)c2cccc(C(F)(F)F)c2)C1=O
Yield: 39.1 %

Procedure:
A solution of (1R,2S,5R)-methyl 2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)-cyclohexanecarboxylate (56 mg, 0.18 mmol), 3-(trifluoromethyl)benzoic acid (42 mg, 0.22 mol), EDCI (42 mg, 0.22 mmol), HOBT (30 mg, 0.22 mmol), and Et3N (22 mg 0.20 mmol) in CH2Cl2 was stirred overnight at room temperature. The solution was washed with water and brine, concentrated in vacuo and the residue chromatographed on silica gel (3%–5%–10% (NH4OH/MeOH)/CH2Cl2) to give 34 mg of the title product, (1R,2S,5R)-methyl 5-(tert-butylamino)-2-((S)-2-oxo-3-(3-(trifluoromethyl)-benzamido)pyrrolidin-1-yl)cyclohexanecarboxylate, as a white solid. MS found: (M+H)+=484.24.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13](/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.[H][H]>C(O)C.[C].[Pd]>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: [H][H]
Reactant: COc1ncccc1CN1CCC(/C=C/c2ccccc2C)CC1
Agent: [Pd]
Solvent: CCO
Product: COc1ncccc1CN1CCC(CCc2ccccc2C)CC1
Yield: 97.7 %

Procedure:
In ethanol (10 ml) was dissolved 473 mg of 1-[(2-methoxy-3-pyridinyl)methyl]-4-[(E)-2-(2-methylphenyl)-1-ethenyl]piperidine. To the mixture was added 100 mg of 10% palladium-carbon powder (water-containing product) was added thereto, followed by stirring at room temperature under normal pressure overnight in a hydrogen atmosphere for 1.5 hours. The reaction solution was filtered, and then the filtrate was evaporated, to give 465 mg of the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[C:3]2[S:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[C:4]=2[C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.O.[CH3:27][N:28](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:25][C:23]1[CH:22]=[CH:21][C:19]2[S:20][C:3]3[C:2]([C:27]#[N:28])=[CH:7][N:6]=[C:5]([NH:8][CH2:9][C:10]4[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=4)[C:4]=3[C:18]=2[CH:24]=1
Reactant: COc1ccc(CNc2ncc(Br)c3sc4ccc(Cl)cc4c23)cc1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: COc1ccc(CNc2ncc(C#N)c3sc4ccc(Cl)cc4c23)cc1
Reaction time: 0.17 h

Procedure:
A mixture containing 4-bromo-8-chloro-N-(4-methoxybenzyl)[1]benzothieno[3,2-c]pyridine-1-amine, Zn(CN)2 (1.2 equiv) and Pd(Ph3P)4 (0.1 equiv) in DMF (0.1 M) was placed in microwave reactor at 150° C. for 10 min. The reaction was poured into H2O, filtered and washed with MeOH.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:3]=1.Cl[C:20]1N=C2C(N=CN2CC)=C(Cl)N=1>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH3:20])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:3]=1
Reactant: CCn1cnc2c(Cl)nc(Cl)nc21
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1ncn2C
Product: CCn1cnc2c(N3CCOC[C@@H]3C)nc(Cl)nc21

Procedure:
The compound (f-4) was prepared in an analogous fashion to (S)-4-(2-chloro-9-methyl-9H-purin-6-yl)-3-methylmorpholine, using 2,6-dichloro-9-ethyl-9H-purine as the starting material. 1H NMR (CDCl3, 400 MHz) δ ppm 7.71 (s, 1H), 5.41 (broad s, 1H), 5.00 (broad s, 1H), 4.19 (q, J=7.4 Hz, 2H), 4.00 (dd, J=7.8, 3.6 Hz, 1H), 3.76 (m, 2H), 3.61 (td, J=11.6, 2.6 Hz, 1H), 3.48 (broad s, 1H), 1.48 (t, J=7.2 Hz, 3H), 1.41 (d, J=6.8 Hz, 3H); LCMS m/z (method A)=284 [M+H]+, RT=2.06 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH:11]2[CH3:16])[CH3:9])=[CH:4][CH:3]=1.[C:17]([N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:20]([O:19][C:17]([N:24]1[CH2:29][CH2:28][CH:27]([N:13]2[CH2:14][CH2:15][N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[CH3:9])[C@H:11]([CH3:16])[CH2:12]2)[CH2:26][CH2:25]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC1CNCCN1C(C)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1CN(C2CCN(C(=O)OC(C)(C)C)CC2)CCN1[C@@H](C)c1ccc(Br)cc1
Reaction time: 0.5 h

Procedure:
The product of step 4 was stirred for 20 h. at RT with N-Boc-4-piperidinone (4.32 g), HOAC (1.15 ml), CH2Cl2 (80 ml) and sodium triacetoxy-borohydride (NaBH(OAc)3) (8.3 g). Thereafter the reaction was quenched with excess aqueous Na2CO3 solution slowly and stirred for 0.5 h. The organic layer was separated and filtered through a pad of silca gel, washing with 10:1 CH2Cl2-Et2O to elute all of the product. The filtate was evaporated and dissolved in Et2O (100 ml). To this was added dropwise a 4M solution of HCl in 1,4-dioxane (10 ml). The solids were collected, washed with Et2O, and stirred with CH2Cl2 and excess aqueous NaOH. The organic phase was dried over K2CO3 and evaporated to obtain 1-tert-butoxycarbonyl-4-{4-[1 (S)-(4-bromophenyl)-ethyl]-3(R)-methylpiperazin-1-yl}-piperidine (5.45 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].S(O[CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH3:49])(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[CH3:49][O:48][CH2:47][CH2:46][O:45][CH2:44][CH2:43][O:42][CH2:41][CH2:40][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Reactant: OCCOCCOCCOCCOCCOCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCCOCCOCCOCCOCCOCCOCCOCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A solution of hexaethylene glycol monobenzyl ether from above (22.3 g) in anhydrous THF (100 ml) was added to a suspension of 50% NaH (3.5 g) in anhydrous THF (100 ml). The suspension was stirred at ambient temperature for 30 min and then a solution of triethylene glycol methyl tosyl ether from above (22.0 g) in THF (100 ml) was added dropwise. The mixture was refluxed under nitrogen overnight, cooled to ambient temperature, quenched with water (500 ml), and extracted with diethyl ether (3×300 ml). The ether extracts were combined, dried (sodium sulfate), and concentrated in vacuo to give nonaethylene glycol benzyl methyl ether as an oil (27 g, 88%), 1H-NMR (CDCl3) δ: 7.31 (m, 5, 5 phenyl CH), 4.54 (s, 2, benzyl CH2), 3.62-3.52 (m, 36, 18 CH2O), 3.35 (s, 3, CH3).
Reaction SMILES: [CH2:1]([C:5]1[C:13]([C:14]([C:16]2[CH:23]=[CH:22]C=C[C:17]=2[C:18]#N)=[O:15])=[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)O.[C:29]([OH:32])(=[O:31])[CH3:30]>O>[CH2:1]([C:5]1[C:13]([C:14]([C:16]2[CH:23]=[CH:22][C:30]([C:29]([OH:32])=[O:31])=[CH:18][CH:17]=2)=[O:15])=[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)O
Reactant: CCCCc1nn2ccccc2c1C(=O)c1ccccc1C#N
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCc1nn2ccccc2c1C(=O)c1ccc(C(=O)O)cc1

Procedure:
A mixture of 845 mg of the product of Example 2 and 15 ml of a mixture in equal proportions of sulfuric acid, acetic acid and water was refluxed for 2 hours and the mixture was cooled down, taken up in water, filtered, washed with water and dried at 80° C. under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[CH2:11]1[CH2:20][O:19][C:13]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[O:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][N:16]1[CH2:17][CH2:18][C:13]2([O:19][CH2:20][CH2:11][O:12]2)[CH2:14][CH2:15]1
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: C1CC2(CCN1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Fc1ccc(CN2CCC3(CC2)OCCO3)cc1F
Yield: 94.9 %

Procedure:
A solution of 3,4-difluorobenzaldehyde (4.40 g, 30.9 mmol), 4,4-ethylenedioxy-piperidine (4.40 g, 30.9 mmol), sodium triacetoxyborohydride (6.40 g, 30.2 mmol) and acetic acid (1.8 g, 30.0 mmol) in dichloroethane (200 ml) was stirred at room temperature for 18 h. After this period, the reaction mixture was washed with 1N sodium hydroxide. The organic layer separated, dried (MgSO4) and the solvents evaporated in vacuo to give D3 (7.9 g, 98%). C14H17F2NO2 requires 269; Found 270 (MH+)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([CH:14]=[O:15])=[CH:5][N:4]=1.[O-:16]Cl=O.[Na+]>C(#N)C.O>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([C:14]([OH:16])=[O:15])=[CH:5][N:4]=1
Reactant: [O-][Cl+][O-]
Reactant: COc1ncc(C=O)c2c(C)cccc12
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1ncc(C(=O)O)c2c(C)cccc12

Procedure:
To a stirred solution of 1-methoxy-5-methylisoquinolin-4-carbaldehyde (Intermediate-7) (2 g, 10 mmol) in ACN—H2O (120 mL, 1:1) was added, NaClO2 (5.4 g, 59.7 mmol), NaH2PO4 (5.5 g, 40 mmol) and the mixture was stirred at RT overnight. It was then extracted with EtOAc (3×150 mL), dried over Na2SO4, filtered and concentrated to give the desired acid derivative (1.2 g, 56%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19][CH3:20])=[O:10].[C:21]([CH2:23][C:24](O)=[O:25])#[N:22].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[NH2:22][C:21]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[C:9](=[O:10])[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19][CH3:20])[C:24](=[O:25])[CH:23]=1
Reactant: CSc1ccccc1CNC(=O)Nc1ccccc1C
Reactant: N#CCC(=O)O
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CSc1ccccc1Cn1c(=O)cc(N)n(-c2ccccc2C)c1=O
Reaction time: 16 h

Procedure:
1-(2-Methylphenyl)-3-[2-(methylthio)benzyl]urea (23.47 g) and cyanoacetic acid (7.66 g) were ground together and acetic anhydride (23 ml) was added. The mixture was stirred and heated at 75°-80° C. for 30 h. Toluene (20 ml) was then added and heating continued for a further 16 hours. The reaction was cooled and filtered. The filtrate was heated to boiling and treated with charcoal. The solid was removed by filtration and the filtrate evaporated in vacuo. The resulting oil was dissolved in dichloromethane (300 ml) and trietbylamine (8.15 g) added. The mixture was stirred for 5 hours at room temperature and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate and the product was recrystallised from ethyl acetate. Yield=2.60 g.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH2:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl[C:31]([O:33][CH:34]=[CH2:35])=[O:32]>ClCCCl>[CH:34]([O:33][C:31]([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:10][CH2:9]1)=[O:32])=[CH2:35]
Reactant: C=COC(=O)Cl
Reactant: C(=C/C1CCN(Cc2ccccc2)CC1)\c1ccccc1OCC1CCCCC1
Solvent: ClCCCl
Product: C=COC(=O)N1CCC(/C=C/c2ccccc2OCC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
2.848 g of 1-benzyl-4-[(E)-2-[(2-cyclohexylmethyloxy)phenyl]-1-ethenyl]piperidine was dissolved in 15 ml of 1,2-dichloroethane, 0.93 ml of vinyl chloroformate was added thereto, and the mixture was stirred at room temperature for 50 minutes and heated under reflux for one hour. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (n-hexane:ethyl acetate=50:1), to give 2.026 g of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:14])=O>>[NH2:1][C:2]1[N:7]=[C:6]([Cl:14])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Nc1ncc([N+](=O)[O-])c(O)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Nc1ncc([N+](=O)[O-])c(Cl)n1

Procedure:
A suspension of 2-amino-4-hydroxy-5-nitropyrimidine (5.0 g, 32.1 mmol) in phosphorous oxychloride (100 mL) was refluxed overnight, and the excess phosphorous oxychloride was evaporated under reduced pressure. The residue was mixed with ice (100 g) in an ice-bath, and the mixture was neutralized with concentrated aqueous sodium carbonate solution. A yellow precipitate was collected by filtration and washed with water: yield, 1.39 g (25%); mp 191°-194° C. dec.; 1H NMR δ8.45 (br s, 2H, NH2, exchange with D2O), 9.03 (s, 1H, H-6); MS (EI) calcd. m/z for C4H3N4O235Cl 173.9944, found 173.9934; calcd. m/z for C4H3N4O237Cl 175.9915, found 175.9916.
Reaction SMILES: Br.[NH2:2][C:3]1[N:7]2[C:8](SC)=[N:9][CH:10]=[C:11]([Cl:12])[C:6]2=[N:5][N:4]=1.[C:15](OCC)(=[O:18])C=C.C[O-].[Na+].C(O)(=O)C>CO>[NH2:2][C:3]1[N:7]=[C:6]2[N:5]([C:8]([O:18][CH3:15])=[N:9][CH:10]=[C:11]2[Cl:12])[N:4]=1
Reactant: C=CC(=O)OCC
Reactant: CSc1ncc(Cl)c2nnc(N)n12
Agent: Br
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ncc(Cl)c2nc(N)nn12
Temperature: 25 °C

Procedure:
A mixture of 15.0 g (51 mmol) of 3-amino-8-chloro-5-methylthio[1,2,4]triazolo[4,3-c]pyrimidine hydrobromide, 8.2 mL (76 mmol) of ethyl acrylate, and 150 mL of methanol was prepared and cooled in an ice bath. A solution of 17 mL (76 mmol) of 4.5 molar sodium methoxide in methanol was added to this slowly with cooling and stirring. When the addition was complete, the mixture was allowed to warm to ambient temperature and was stirred for 18 hours. It was then neutralized with 2.0 mL of acetic acid. The solids that formed were recovered by filtration, washed with diethyl ether, and dried to obtain 7.7 g (75 percent of theory) of the title compound as a tan powder melting above 250° C. 1H NMR (DMSO-d6): δ 8.0(s, 1H); 6.6 (brs, 2H); 4.1 (s, 3H); 13C: δ 166.40, 151.65, 147.73:, 140.95, 108.57, 56.12. Anal. Calc'd for C6H6N5ClO: C, 36.1; H, 3.03; N, 35.1. Found: C, 36.1; H, 3.19; N, 34.8.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH3:17])=[CH:13][CH:14]=2)[C:9]1=[O:18])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH3:17])=[CH:13][CH:14]=2)[C:9]1=[O:18]
Reactant: O=[O+][O-]
Reactant: CC=CCC1Cc2ccc(C)cc2C1=O
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc2c(c1)C(=O)C(CC=O)C2
Reaction time: 1.33 h
Yield: 82 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 80 minutes while stirring through a solution, cooled to -70°, of 16.3 g of (RS)-2-(2-buten-1-yl)-6-methyl-1-indanone in 300 ml of anhydrous dichloromethane and 60 ml of anhydrous methanol. Subsequently, the mixture was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 8.95 ml of dimethyl sulfide, the mixture was stirred at room temperature for 15 hours. The reaction mixture was evaporated in a vacuum, the residue was treated with 300 ml of dichoromethane and, after the addition of 40 ml of water and 40 ml of trifluoroacetic acid, stirred at room temperature for 3 hours. The mixture was subsequently poured into 200 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 100 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 200 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. The crude product obtained was recrystallized from diethyl ether/hexane. 12.7 g (82%) of (RS)-2-(2-oxoethyl)-6-methyl-1-indanone were obtained as a light yellow solid with m.p. 53°-54°.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[C:5]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH:6]=[C:7]([O:10][CH2:11][C@H:12]([OH:28])[CH2:13][NH:14][C:15]([CH3:27])([CH3:26])[CH2:16][CH:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18]2)[C:8]=1[F:9].Cl.[CH2:35](O)[CH3:36]>C(OCC)C>[ClH:1].[CH2:35]([O:32][C:31](=[O:33])[CH2:30][CH2:29][C:5]1[CH:6]=[C:7]([O:10][CH2:11][C@H:12]([OH:28])[CH2:13][NH:14][C:15]([CH3:27])([CH3:26])[CH2:16][CH:17]2[CH2:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:25]2)[C:8]([F:9])=[C:3]([F:2])[CH:4]=1)[CH3:36].[ClH:1]
Reactant: CC(C)(CC1Cc2ccccc2C1)NC[C@@H](O)COc1cc(CCC(=O)O)cc(F)c1F
Reactant: CCO
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)CCc1cc(F)c(F)c(OC[C@H](O)CNC(C)(C)CC2Cc3ccccc3C2)c1
Temperature: 25 °C

Procedure:
To a suspension of the propionic acid of Example 2 (2 g) in ethanol (20 mL) was added 2M HCl in diethyl ether (2 mL). The mixture was heated to reflux for 3 h. After cooling to RT, the resulting solution was concentrated to a yellow oil and dried under vacuum. The contents of the flask solidified to give the title compound as an HCl salt (2 g): 1H NMR (dmso-d6): δ 9.05 (m, 1H); 8.62 (m, 1H); 7.18 (m, 2H); 7.11 (m, 2H); 6.98 (app. d, J=7.1 Hz, 1H); 6.91 (m, 1H); 6.0 (br s, 1H); 4.27 (m, 1H); 4.14 (d, J=5.2 Hz, 2H); 4.06 (q, J=7.1 Hz, 2H); 3.18 (m, 1H); 3.09 (m, 2H); 2.98 (m, 1H); 2.82 (t, J=7.5 Hz, 2H); 2.61 (m, 5H); 1.97 (d, J=5.4 Hz, 2H); 1.39 (s, 6H); 1.17 (t, J=7.1 Hz, 3H): LCMS (m/z) M+H=476.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:16]([NH:19][C:20](=[CH2:25])[C:21]([O:23][CH3:24])=[O:22])(=[O:18])[CH3:17].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:16]([NH:19][C:20](=[CH:25][C:5]1[CH:4]=[C:3]([C:2]([F:15])([F:14])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1)[C:21]([O:23][CH3:24])=[O:22])(=[O:18])[CH3:17]
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Reactant: C=C(NC(C)=O)C(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C(=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)NC(C)=O
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Under a nitrogen atmosphere 50.0 g (171 mmol) 3,5-bis-(trifluoromethyl)-bromobenzene, 25.0 g (171 mmol) methyl 2-acetylamino-acrylate in 475 mL triethylamine and 250 mL acetonitrile were combined with 3.9 g (12.4 mmol) tri-o-tolyl-phosphane and 2.8 g (12.5 mmol) Pd(OAc)2 and stirred for 18 h at 80° C. After the reaction had ended the reaction mixture was evaporated down i. vac. to approx. 200 mL, combined with 400 mL EtOAc and 400 mL water, the precipitate was suction filtered and the phases were separated. The organic phase was dried over Na2SO4, combined with activated charcoal, filtered and evaporated to dryness. The residue was stirred with DIPE, suction filtered and dried i. vac.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](O)=[O:17])=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:24])=O.CN(C=O)C>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([Cl:24])=[O:17])=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(CC(=O)O)ccc1OCc1ccccc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc(CC(=O)Cl)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-benzyloxy-3-methoxyphenylacetic acid (5.0 g, 18 mmol), from Step 2, in THF (40 mL) was added oxalyl chloride (2.54 g, 20 mmol, 1.1 equivalent) followed by a catalytic amount of DMF (~0.2 mL). The resulting mixture was stirred at ambient temperature for 2 hours and then concentrated under reduced pressure to give the title compound which was used without purification.