Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH2:20].C(N(CC)CC)C>O1CCCC1>[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:20]([CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[C:16]([Cl:15])[CH:17]=2)[CH:10]=1
Reactant: NCc1cccc(Cl)c1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N=c1c(C(N)=O)cc(Cl)cn1Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.4 %

Procedure:
To a solution of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.5 g) in tetrahydrofuran (10 ml) was added a solution of 3-chlorobenzylamine (0.45 g) (Table 1-1, amine 19) and triethylamine (0.32 g) in tetrahydrofuran (3 ml) under ice-cooling, and the mixture was allowed to warm to room temperature and stirred for 18 hr. The reaction mixture was concentrated, and the crystals were collected by filtration. The obtained crystals were added to a mixture of dimethylsulfoxide (5 ml)-water (5 ml), and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was concentrated, the residue was purified by preparative HPLC, and the obtained fraction was treated with PL-HCO3MP (200 mg cartridge, Polymer Laboratories) to give the title compound (0.33 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[C:5]([C:18]([F:21])([F:20])[F:19])[CH:4]=1.[H][H]>N.[Ni]>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH2:12][NH2:13])=[CH:10][CH:9]=2)=[C:5]([C:18]([F:19])([F:20])[F:21])[CH:4]=1
Reactant: COc1ccc(Oc2ccc(C#N)cc2)c(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Product: COc1ccc(Oc2ccc(CN)cc2)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
2.53 g (8.63 mmol) of 4-(4-methoxy-2-trifluoromethyl-phenoxy)-benzonitrile (from 82c) were dissolved in 100 ml 7M methanolic ammonia, then combined with 250 mg Raney nickel. The mixture was shaken at RT and 50 psi hydrogen pressure for 3 h. The catalyst was removed by suction filtering and the filtrate was evaporated down.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][CH2:10][C:11]1[C:19]3[C:18]([C:20]([O:22]C)=[O:21])=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][N:12]=1)[CH2:2]2.O.O.[OH-].[Li+:27]>C1COCC1>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[C@@H:3]([NH:9][CH2:10][C:11]1[C:19]3[C:18]([C:20]([O-:22])=[O:21])=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][N:12]=1)[CH2:2]2.[Li+:27]
Reactant: COC(=O)c1cccc2[nH]nc(CN[C@H]3CN4CCC3CC4)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C([O-])c1cccc2[nH]nc(CN[C@H]3CN4CCC3CC4)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-methyl 3-((quinuclidin-3-ylamino)methyl)-1H-indazole-4-carboxylate (1.8 g, 5.7 mmol) from Step A above in THF (30 ml) and H2O (30 ml) was added lithium hydroxide monohydrate (721 mg, 17.2 mmol). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was dried overnight under vacuum to afford crude lithium (R)-3-((quinuclidin-3-ylamino)methyl)-1H-indazole-4-carboxylate which was used in the next step without further purification: MS (ESI+) m/z 301 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12](=O)[CH:11](Br)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([NH2:20])(=[S:19])[CH3:18].C(N(CC)CC)C>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[S:19][C:17]([CH3:18])=[N:20][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(Br)CC1
Reactant: CC(N)=S
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nc2c(s1)CCN(C(=O)OC(C)(C)C)CC2

Procedure:
The title compound was prepared by the following reaction sequence: i) treatment of the 5-bromo-azepan-4-one hydrobromide (1:1) [Ger. Offen. (1989), DE 38207751] with di-t-butyldicarbonate in dioxane/aq. sodium hydrogen carbonate solution to yield the 4-bromo-5-oxo-azepane-1-carboxylic acid tert-butyl ester; ii) treatment of the 4-bromo-5-oxo-azepane-1-carboxylic acid tert-butyl ester with thioacetamide in ethanol in the presence of triethylamine at reflux to give the 2-methyl-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepine-6-carboxylic acid tert-butyl ester; iii) conversion of the 2-methyl-4,5,7,8-tetrahydro-thiazolo[5-d]azepine-6-carboxylic acid tert-butyl ester into the 2-methyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine by removal of the tert-butyloxycarbonyl function with hydrogen chloride (aqueous, 37%) in methanol at room temperature.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:8].[Li][CH2:10]CCC.CI>C1COCC1>[CH3:10][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][NH:1][C:2]1=[O:8]
Reactant: O=C1CCCCCN1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CC1CCCCNC1=O
Reaction time: 2 h

Procedure:
To a solution of azepan-2-one (0.5 g, 4.42 mmol, 1 equiv) in anhydrous THF (20 mL) under nitrogen, was added n-BuLi (4.4 mL, 2.5 M in n-hexane, 11.06 mmol) dropwise at 0° C. The reaction mixture was kept at 0° C. for 2 h, then MeI (0.3 mL, 4.86 mmol) was added. After stirring for 1 h, the mixture was quenched with water and extracted with DCM (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration and concentration, the crude product was directly used for the next step without further purification. MS (ESI): 128 (MH+).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([O:25][CH2:26][CH3:27])[C:22]([OH:24])=O)=[CH:16][CH:15]=2)[CH2:3][CH2:2]1.[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([NH:35][C:22](=[O:24])[CH:21]([O:25][CH2:26][CH3:27])[CH2:20][C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:12][CH2:11][N:4]2[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[O:1][CH2:2][CH2:3]2)=[CH:19][CH:18]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCc1ccccc1
Reactant: CCOC(Cc1ccc(OCCN2CCOc3ccccc32)cc1)C(=O)O
Product: CCOC(Cc1ccc(OCCN2CCOc3ccccc32)cc1)C(=O)NCc1ccccc1
Yield: 67.9 %

Procedure:
The title compound (0.25 g, 67%) was prepared as a white solid from 3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (0.3 g, 0.8 mmol) obtained in example 26 and benzyl amine (0.095 g, 0.88 mmol) by a procedure analogous to that described in example 32. mp: 94-96° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=O)[CH:41]=5)[C:36]([F:39])=[CH:37][CH:38]=4)=[O:30])[N:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:50][C@@H:51]1[CH2:56][NH:55][CH2:54][C@H:53]([CH3:57])[NH:52]1.C(O)(=O)C>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:55]6[CH2:54][C@H:53]([CH3:57])[NH:52][C@H:51]([CH3:50])[CH2:56]6)[CH:41]=5)[C:36]([F:39])=[CH:37][CH:38]=4)=[O:30])[N:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(C=O)c3)c2)n1
Reactant: C[C@@H]1CNC[C@H](C)N1
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4C[C@@H](C)N[C@@H](C)C4)c3)c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.5 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-formyl-3-biphenylyl)methyl]-2,6-pyridinedicarboxamide (0.059 mmol) was diluted in DMSO (1.5 mL) and dispensed into a 1 dram vial containing (2R,6S)-2,6-dimethylpiperazine (0.177 mmol, 3.0 eq) and acetic acid (3.55 mg, 0.059 mmol) and fitted a magnetic stir bar. The resulting solution was stirred at room temperature for 4 h. MP-B(OAc)3H (0.591 mmol, 138 mg, 10.0 eq) was added and the solution was stirred for another 12 h. The polymer reagent was filtered. Purification was completed via a Gilson HPLC (acidic conditions). The product was dissolved in 3 mL of MeOH and passed through 0.5 g amine columns (washed with 8 mL of MeOH) to afford 29.9 mg of the title compound (66.5%). LC-MS m/z 763 (M+H)+, 1.31 min (ret time).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:16])([CH3:15])[CH2:9]OS(C)(=O)=O)[C:5]([F:17])=[CH:4][CH:3]=1.[Cl-].[NH4+].[N-:20]=[N+:21]=[N-:22].[Na+]>C(O)C.C(OCC)(=O)C>[N:20]([CH2:9][C:8]([C:6]1[C:5]([F:17])=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1)([OH:16])[CH3:15])=[N+:21]=[N-:22]
Reactant: CC(O)(COS(C)(=O)=O)c1nc(Br)ccc1F
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(O)(CN=[N+]=[N-])c1nc(Br)ccc1F
Temperature: 80 °C
Reaction time: 20 h
Yield: 74 %

Procedure:
A mixture of methanesulfonic acid 2-(6-bromo-3-fluoro-pyridin-2-yl)-2-hydroxy-propyl ester (5 g, 15.24 mmol), ammonium chloride (4.08 g, 76 mmol) and sodium azide (2.476 g, 38.1 mmol) in ethanol (100 ml) was stirred at 80° C. for 20 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate, filtered and evaporated. 3.1 g (74% yield). TLC (cyclohexane/ethyl acetate 9:1) Rf=0.35; LCMS RtH5=0.97 min. (ES+ 275, 277); 1H-NMR (360 MHz, CDCl3): 7.51 (dd, 1H), 7.36 (dd, 1H), 5.18 (s broad, 1H, OH), 3.68-3.60 (AB system, 2H), 1.59 (s, 3H, CH3).
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[C:13]2[C:8](=[C:9]([O:14][CH3:15])[CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([C:16]([N:18]2[CH2:23][CH2:22][C:21]3([CH2:32][C:31](=[O:33])[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:34]5[NH:38][N:37]=[N:36][N:35]=5)[CH:29]=4)[O:24]3)[CH2:20][CH2:19]2)=[O:17])[CH:5]=1.[C:39]([O:45][CH2:46]Cl)(=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41]>CN(C=O)C.C(OCC)(=O)C>[C:39]([O:45][CH2:46][N:36]1[N:37]=[N:38][C:34]([C:28]2[CH:29]=[C:30]3[C:25](=[CH:26][CH:27]=2)[O:24][C:21]2([CH2:22][CH2:23][N:18]([C:16]([C:6]4[CH:5]=[C:4]([O:3][CH3:2])[C:13]5[C:8](=[C:9]([O:14][CH3:15])[CH:10]=[CH:11][CH:12]=5)[N:7]=4)=[O:17])[CH2:19][CH2:20]2)[CH2:32][C:31]3=[O:33])=[N:35]1)(=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41]
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnn[nH]4)ccc2O3)nc2c(OC)cccc12
Reactant: CC(C)(C)C(=O)OCCl
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnn(COC(=O)C(C)(C)C)n4)ccc2O3)nc2c(OC)cccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of the sodium salt (105 mg) obtained in Example 18 in 1.0 mL of DMF, was added pivaloyloxymethyl chloride (35.6 μl), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with 20 mL of ethyl acetate, washed with water (4 times) and aqueous saturated sodium chloride solution, then dried over sodium sulfate, and concentrated. The residue was purified through silica gel column chromatography (0.7% methanol/chloroform) to obtain the 2-isomer and 1-isomer. 2-Isomer (major product): 1H-NMR (CDCl3) δ: 8.69 (1H, d, J=2.4 Hz), 8.32 (1H, dd, J=2.4, 8.8 Hz), 7.77 (1H, dd, J=1.0, 8.3 Hz), 7.47 (1H, dd, J=7.7, 8.3 Hz), 7.20 (1H, s), 7.16 (1H, d, J=8.8 Hz), 7.08 (1H, d, J=7.7 Hz), 6.50 (2H, s), 4.64-4.56 (1H, m), 4.24-4.17 (1H, m), 4.08 (3H, s), 4.03 (3H, s), 3.68-3.59 (1H, m), 3.40 (1H, td, J=12.9, 2.8 Hz), 2.88 (1H, d, J=16.6 Hz), 2.81 (1H, d, J=16.6 Hz), 2.28-2.20 (1H, m), 2.14-2.07 (1H, m), 2.01-1.88 (2H, m), 1.23 (9H, s). MS [M+H]+=615. 1-Isomer (minor product): 1H-NMR (CDCl3) δ: 8.30 (1H, d, J=2.4 Hz), 8.09 (1H, dd, J=8.8, 2.4 Hz), 7.78 (1H, dd, J=8.2, 1.0 Hz), 7.48 (1H, t, J=8.2 Hz), 7.25 (1H, d, J=8.2 Hz), 7.20 (1H, s), 7.08 (1H, d, J=8.8 Hz), 6.32 (1H, d, J=11.2 Hz), 6.29 (1H, d, J=11.2 Hz), 4.65-4.57 (1H, m), 4.28-4.20 (1H, m), 4.09 (3H, s), 4.04 (3H, s), 3.69-3.59 (1H, m), 3.40 (1H, td, J=12.8, 2.9 Hz), 2.90 (1H, d, J=16.6 Hz), 2.84 (1H, d, J=16.6 Hz), 2.28-2.21 (1H, m), 2.14-2.07 (1H, m), 2.06-1.89 (2H, m), 1.28 (9H, s). MS [M+H]+=615.
Reaction SMILES: C1([O:6][C:7](=[O:35])[C@@H:8]([NH:13][C:14](=[O:34])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:33])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](=[O:32])[NH:30][OH:31])=[CH:17][CH:16]=2)[CH2:9][CH:10]([CH3:12])[CH3:11])CCCC1.[OH-].[Na+].N#N>C1COCC1>[OH:31][NH:30][C:29]([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][C:22]([NH:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]([NH:13][C@@H:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7]([OH:35])=[O:6])=[O:34])=[CH:20][CH:19]=1)=[O:33])=[O:32]
Reactant: CC(C)C[C@H](NC(=O)c1ccc(NC(=O)CCCCCCC(=O)NO)cc1)C(=O)OC1CCCC1
Agent: N#N
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)c1ccc(NC(=O)CCCCCCC(=O)NO)cc1)C(=O)O
Yield: 28.7 %

Procedure:
Compound (98) (21 mg, 0.043 mmol) was dissolved in THF (1 ml) and 2M NaOH (1 ml) added. The reaction vial was shaken for 16 h before THF removal by blowing a stream of N2 gas at the surface of the solution. The aqueous residue was purified by preparative HPLC to yield compound (99) (5.2 mg). LCMS purity 92%, m/z 422 [M++H]+, 1H NMR (400 MHz, MeOD), δ: 0.95-1.05 (6H, m, 2×CH3), 1.30-1.50 (4H, m, alkyl), 1.55-1.85 (7H, m, alkyl), 2.10 (2H, t, CH2), 2.40 (2H, t, CH2), 4.65 (1H, m, CH), 7.65 (2H, d, Ar), 7.80 (2H, d, Ar).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][NH:6][N:5]=1)[CH3:3].[CH3:13][O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.N1C=CC=CC=1>CN(C)C(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([N:6]2[CH:7]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:4]([CH:2]([CH3:1])[CH3:3])=[N:5]2)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: COC(=O)c1c[nH]nc1C(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cn(-c2cccc(OC)c2)nc1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
Methyl 3-(1-methylethyl)-1H-pyrazole-4-carboxylate (2.8 g) synthesized in Example 7(1) was dissolved in N,N-dimethylacetamide (50 mL), 3-methoxyphenylboronic acid (5.0 g), copper acetate (6.0 g) and pyridine (5.3 mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1N hydrochloric acid (50 mL) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (3.4 g, 75%) as a pale-yellow oil.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]([OH:12])=[O:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:13]N1C(=O)CCC1=O>CN(C)C=O.O>[Cl:13][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[C:8]([C:10]([OH:12])=[O:11])[CH:9]=2)[NH:1][CH:2]=1
Reactant: O=C(O)c1cnc2[nH]ccc2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cnc2[nH]cc(Cl)c2c1
Temperature: 40 °C
Reaction time: 5 h
Yield: 54.6 %

Procedure:
A suspension of 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (250 mg, 1.5 mmol) in N,N-dimethylformamide (5 mL) was warmed to 40° C. N-chlorosuccinimide (243 mg, 1.62 mmol) was added and the mixture was stirred at 55° C. for 5 hours. The reaction was cooled to room temperature and left stirring for 2 days. The mixture was diluted with water (20 mL) and stirred overnight. The resulting solid was collected by filtration and dried to give the title compound (161 mg, 55%). +ESI (M+H) 197.1; 1H NMR (400 MHz, DMSO-d6, δ): 13.08 (br. s., 1H), 12.39 (br. s., 1H), 8.86 (d, J=1.8 Hz, 1H), 8.40 (d, J=1.2 Hz, 1H), 7.84 (d, J=2.5 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[O:8][CH2:7][CH2:6][CH:5]2[C:13]([O:15][CH3:16])=[O:14].[CH3:17][N:18]1CCCC1=O>>[C:17]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[O:8][CH2:7][CH2:6][CH:5]2[C:13]([O:15][CH3:16])=[O:14])#[N:18]
Reactant: COC(=O)C1CCOc2cc(F)c(Br)cc21
Reactant: CN1CCCC1=O
Product: COC(=O)C1CCOc2cc(F)c(C#N)cc21
Temperature: 160 °C
Yield: 77 %

Procedure:
Methyl 6-bromo-7-fluoro-3,4-dihydro-2H-chromene-4-carboxylate (415 mg, 1.44 mmol) was diluted with N-methylpyrrolidone (5 mL) followed by the addition of Cu(I)CN (643 mg, 7.18 mmol). The reaction was bubbled with argon for 20 minutes, then heated at 160° C. under a slight argon bubble for 6 hours. The reaction was cooled to ambient temperature and loaded directly onto a Biotage 25 column eluting with 5% ethyl acetate/hexanes to 100% ethyl acetate to yield the title compound (260 mg, 77.0% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.I[C:24]1[CH:25]=[C:26]([C:31]([F:34])([F:33])[F:32])[C:27]([NH2:30])=[N:28][CH:29]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:24]4[CH:25]=[C:26]([C:31]([F:34])([F:33])[F:32])[C:27]([NH2:30])=[N:28][CH:29]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Reactant: Nc1ncc(I)cc1C(F)(F)F
Product: Nc1ncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)cc4)nc23)cc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.4) (322 g, 1.0 mmol) and 5-iodo-3-trifluoromethyl-pyridin-2-ylamine (example B.48) (288 mg, 1.0 mmol) according to general procedure II. Obtained as an orange solid (290 mg, 60%). MS (ISP) 482.3 [(M+H)+], 484 [(M+2+H)+]; mp 209° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([CH2:13][CH3:14])[O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[Mg].Cl[CH:17]1[CH2:21][CH2:20][CH:19]=[CH:18]1>O1CCCC1>[CH:21]1([CH2:2][CH2:3][CH:4]([CH2:13][CH3:14])[O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[CH2:20][CH2:19][CH:18]=[CH:17]1
Reactant: ClC1C=CCC1
Reactant: CCC(CCCl)O[Si](C)(C)C(C)(C)C
Agent: [Mg]
Solvent: C1CCOC1
Product: CCC(CCC1C=CCC1)O[Si](C)(C)C(C)(C)C

Procedure:
Further following the procedure described in Example 6B, substituting 3-chloro-1-ethylpropoxy(1,1-dimethylethyl)dimethylsilane (78 g, 0.33 moles) diluted in tetrahydrofuran (100 ml), granular magnesium (24 g, 1.00 moles), tetrahydrofuran (100 ml), 0.1M solution of Li2CuCl4 (1.0 mmole), and 3-chlorocyclopentene (33 g, 0.33 moles) dissolved in tetrahydrofuran (50 ml), one obtains [3-(2-cyclopenten-1-yl)-1-ethylpropoxy](1,1-dimethylethyl)dimethylsilane. The crude product is distilled under reduced pressure leaving a clear yellow oil (21 g, 0.078 moles), BP 69° C./0.1 mm.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:13]([C:14]2([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15]2)[CH2:12][N:11]([C@H:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:23])[C:10]1=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>C1C=CC=CC=1>[Si:1]([O:8][C@@H:9]1[C@@H:13]([C:14]2([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15]2)[CH2:12][N:11]([C@H:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:23])[C:10]1=[S:40])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=O)[C@@H]2O[Si](C)(C)C(C)(C)C)CC1
Solvent: c1ccccc1
Product: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=S)[C@@H]2O[Si](C)(C)C(C)(C)C)CC1
Yield: 88 %

Procedure:
3-(R)-Tert-butyldimethylsilyloxy-4-(S)-(1-ethoxycarbonylcyclopropyl)-1-[1-(S)-phenylethyl]-2-pyrrolidone was dissolved in dry benzene (200 ml), and the solution was mixed with Lawesson's reagent (4.49 g, 11.1 mmol) and heated under reflux for 3 hours. After cooling, benzene was evaporated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography and eluted with an eluant of n-hexane:ethyl acetate=4:1, to thereby obtain 7.96 g (88%) of the title compound as a light yellow oil.
Reaction SMILES: [N+](=[CH:3][C:4]([CH:6]1[O:12][CH:11]2[C:8]([C:34](=[O:42])[CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:9](=[O:33])[N:10]2[C:13](=[C:30]([CH3:32])[CH3:31])[C:14]([O:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[NH:7]1)=[O:5])=[N-].B(F)(F)F.CCOCC.[C:52]([OH:55])(=[O:54])[CH3:53]>>[C:52]([O:55][CH2:3][C:4]([CH:6]1[O:12][CH:11]2[C:8]([C:34](=[O:42])[CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:9](=[O:33])[N:10]2[C:13](=[C:30]([CH3:31])[CH3:32])[C:14]([O:16][CH:17]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[NH:7]1)=[O:5])(=[O:54])[CH3:53]
Reactant: CC(=O)O
Reactant: CC(C)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2(C(=O)Cc3ccccc3)NC(C(=O)C=[N+]=[N-])OC12
Agent: FB(F)F
Solvent: CCOCC
Product: CC(=O)OCC(=O)C1NC2(C(=O)Cc3ccccc3)C(=O)N(C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C)C)C2O1
Temperature: 0 °C
Yield: 30 %

Procedure:
To a solution of 200 mg of diphenylmethyl α-(3ξ-diazoacetyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]-heptan-6-yl)-α-isopropylideneacetate in 2 ml of acetic acid is added 0.045 ml of boron trifluoride etherate. After the termination of gas evolution, the reaction mixture is poured into ice water and extracted with ethyl acetate. The extract is washed with water, an aqueous solution of sodium hydrogencarbonate and then water, dried on sodium sulfate and evaporated. The residue (205 mg) is purified by thin-layer chromatography to yield 65 mg of diphenylmethyl α-(3ξ-acetoxyacetyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 30% yield.
Reaction SMILES: [Se](=O)=[O:2].[Cl:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:15])=[CH:10][CH:11]=[N:12]2)=[CH:7][CH:6]=1>O1CCOCC1.O>[Cl:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH:15]=[O:2])=[CH:10][CH:11]=[N:12]2)=[CH:7][CH:6]=1
Reactant: O=[Se]=O
Reactant: Cc1ccnc2cc(Cl)ccc12
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1ccnc2cc(Cl)ccc12
Temperature: 85 °C
Reaction time: 6 h
Yield: 74.7 %

Procedure:
Selenium dioxide (4.52g; 40.3mmol) in a mixture of 25ml of dioxane and 6ml of water was added in a dropwise fashion to 7-chlorolepidine (6; 6.50g; 36.6mmol) in 25ml of dioxane to 65 °-75° C. The temperature was raised to 85° C. and maintained there with stirring for 6 hours. After cooling, the mixture was filtered through Celite™ and concentrated. The crude material was purified on a flash column, eluting with 10% ethyl acetate/hexane to obtain 5.24g (74%) of aldehyde 7 as a yellow solid. 1H NMR (CDCl3): δ7.68 (d, 1H); 7.79 (d, 1H); 8.19 (d, 1H); 9.01 (dd, 1H); 9.21 (m, 1H); 10.45 (s, 1H). IR (KBr): 1702, 1499, 1216, 1041, 900, 653 cm-1.
Reaction SMILES: [C:1]1([C:7]2([OH:20])[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1.O>CS(C)=O>[C:1]1([C:7]2([O:20][C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: Clc1cnccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc(CN2CCC(Oc3cnccn3)(c3ccccc3)CC2)cc1
Reaction time: 24 h
Yield: 18.8 %

Procedure:
A solution of 4-phenyl-1-phenylmethyl-4-piperidinol (5.35 g, 20 mM) in DMSO (50 ml) was treated with sodium hydride (960 mg of a 50% dispersion, 20 mM) followed by chloropyrazine (2.29 g, 20 mM); the reaction was stirred for 24 hours and then poured on to water (200 ml). The aqueous layer was extracted with ether (3×100 ml), the combined organic phases washed with water (100 ml) and dried. Removal of the solvents under reduced pressure followed by recrystallisation gave the title compound (1.3 g), m.p. 107°-8° C.