Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1.[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:13]1[CH:17]=[N:16][C:15]([C:3]2[O:4][C:5]3[C:10]([C:11](=[O:12])[CH:2]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[N:14]1
Reactant: O=c1c(I)coc2ccccc12
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc(-c2nc[nH]n2)oc2ccccc12
Temperature: 0 °C
Yield: 63.8 %

Procedure:
To an eggplant type flask (25 ml), 3-iodochromone (136 mg) prepared in Example 1, 1,2,4-triazole (138 mg), potassium carbonate (1382 mg), and dimethylformamide (15 ml) were added and the mixture was reacted at 80° C. for 2 hours with stirring. The reaction mixture was added to ice water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purifiedby the silica gel column chromatography, and the purified compound was recrystallized from benzene/hexane to give the titled compound (68 mg; yield =63.8%) as white needle crystals. Melting point: 210° C. 1H-NMR(CDCl3, δ ppm): 6.90 (s, H3), 8.26 (dd, H5), 7.47-7.60 (m, H6), 7.77 (t, H7), 7.47-7.60 (m, H8), 8.19 (s, H3'), 8.91 (s, H5').
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[CH:6]=[C:7]([C:11]2[C:12]3[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[N:20][C:13]=3[N:14]([CH2:18][CH3:19])[C:15](=[O:17])[N:16]=2)[CH:8]=[CH:9][CH:10]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:4][C:5]1[CH:6]=[C:7]([C:11]2[C:12]3[CH:23]=[CH:22][C:21]([CH:24]([OH:25])[CH3:1])=[N:20][C:13]=3[N:14]([CH2:18][CH3:19])[C:15](=[O:17])[N:16]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: C[Mg]Br
Reactant: CCn1c(=O)nc(-c2cccc(Cl)c2)c2ccc(C=O)nc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCn1c(=O)nc(-c2cccc(Cl)c2)c2ccc(C(C)O)nc21
Reaction time: 0.5 h
Yield: 30.3 %

Procedure:
1 M Methylmagnesium bromide (14 ml, 14 mmol) was added to a solution of 4.4 g (14 mmol) of 4-(3-chlorophenyl)-1-ethylpyrido[2,3-d]pyrimidin-2(1H)-one-7-carbaldehyde in 50 ml of tetrahydrofuran under ice-cooling, followed by stirring for 30 minutes under ice-cooling. Then, 7 ml (7 mmol) of 1 M methylmagnesium bromide was added and the mixture was stirred for 30 minutes under ice-cooling. Then, saturated ammonium chloride aqueous solution was added, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, magnesium sulfate was removed by filtration and the resulting filtrate was concentrated under a reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate-chloroform) to give 1.4 g of 4-(3-chlorophenyl)-1-ethyl-7-(1-hydroxyethyl)pyrido[2,3-d]pyrimidin-2(1H)-one. The yield was 30%.
Reaction SMILES: [C:1]([C@@H:3]([NH:22][C:23]([C:25]1([NH:31]C(=O)OC(C)(C)C)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:21]=[CH:20][C:14]3[CH2:15][S:16](=[O:19])(=[O:18])[CH2:17][C:13]=3[CH:12]=2)=[CH:7][CH:6]=1)#[N:2].C(O)=O>CO>[NH2:31][C:25]1([C:23]([NH:22][C@H:3]([C:1]#[N:2])[CH2:4][C:5]2[CH:6]=[CH:7][C:8]([C:11]3[CH:21]=[CH:20][C:14]4[CH2:15][S:16](=[O:19])(=[O:18])[CH2:17][C:13]=4[CH:12]=3)=[CH:9][CH:10]=2)=[O:24])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(-c3ccc4c(c3)CS(=O)(=O)C4)cc2)CCOCC1
Solvent: CO
Solvent: O=CO
Product: N#C[C@H](Cc1ccc(-c2ccc3c(c2)CS(=O)(=O)C3)cc1)NC(=O)C1(N)CCOCC1
Temperature: 50 °C
Yield: 33.6 %

Procedure:
To tert-butyl [4-({(1S)-1-cyano-2-[4-(2,2-dioxido-1,3-dihydro-2-benzothiophen-5-yl)phenyl]ethyl}carbamoyl)tetrahydro-2H-pyran-4-yl]carbamate (Example 34, step (ii), 300 mg) was added formic acid (2 mL) and the mixture heated to 50° C. for 30 min. The mixture was allowed to cool to room temperature and then methanol (5 mL) was added and the mixture evaporated to give an oil. The crude mixture was purified by preparative HPLC (SunFire column) eluting with methanol/0.1% aqueous trifluoroacetic acid to afford a product which was then purified by chromatography on silica eluting with ethyl acetate to give the titled compound (82 mg).
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14])([O:3][CH2:4][CH3:5])=[O:2].[C:15](OC(=O)C)(=[O:17])[CH3:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:15]([O:14][C:10]1[CH2:11][CH2:12][CH2:13][C:9]=1[CH2:8][CH2:7][CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])(=[O:17])[CH3:16]
Reactant: CCOC(=O)CCCC1CCCC1=O
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)CCCC1=C(OC(C)=O)CCC1

Procedure:
In the manner described in Example 10, treatment of 2-(3-carbethoxypropyl)cyclopentan-1-one (Example 6) with acetic anhydride and p-toluenesulfonic acid monohydrate gives a yellow oil, b.p. 98°-103° C. (0.35 mm).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH2:23]([OH:25])[CH3:24].[H-].[Na+].O>CS(C)=O>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([NH:12][C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[C:2]([O:25][CH2:23][CH3:24])=[N:3][CH:4]=[CH:5]3)(=[O:15])=[O:14])=[CH:17][CH:18]=1
Reactant: CCO
Reactant: O=S(=O)(Nc1ccc2c(Cl)nccc2c1)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOc1nccc2cc(NS(=O)(=O)c3ccc(Cl)cc3)ccc12
Temperature: 80 °C
Reaction time: 9 h

Procedure:
1-Chloro-6-(4-chlorobenzenesulfonylamino)isoquinoline (Synthetic Example 61b, 57 mg) was dissolved in dimethyl sulfoxide (1 ml). Ethanol (0.1 ml) and 60% sodium hydride (14 mg) were added thereto, followed by heating under stirring at 80° C. for 9 hours. After cooling as it was, water was added thereto, followed by extracting with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by preparative TLC and solidified using isopropyl ether, to give the title compound (21 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[CH2:13][OH:14].[C:18](OC(=O)C)(=[O:20])[CH3:19].Cl>N1C=CC=CC=1>[C:18]([O:14][CH2:13][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[CH2:6][C:5]1[CH:15]=[CH:16][CH:17]=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:20])[CH3:19]
Reactant: COc1cccc(CC2CCCCC2CO)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: COc1cccc(CC2CCCCC2COC(C)=O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of [2-(3-methoxybenzyl)cyclohexyl]methanol (1.5 g) in pyridine (7.5 mL) was added acetic anhydride (4.1 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and at ambient temperature for 1 hour. The reaction mixture was added 1M HCl aqueous solution and was extracted with EtOAc. The organic layer was washed with 1M HCl aqueous solution and saturated NaHCO3 aqueous solution, and brine. The organic layer was dried over anhydrous MgSO4, filtered and evaporated in vacuo to afford [2-(3-methoxybenzyl)cyclohexyl]methyl acetate (1.57 g) as a colorless oil.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:61][C:62]1[O:66][CH:65]=[CH:64][CH:63]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:61][C:62]3[O:66][CH:65]=[CH:64][CH:63]=3)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: N=C(OCc1ccco1)C(Cl)(Cl)Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCc4ccco4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone (63 mg in 1.0 ml methylene chloride) furfuryl trichloroacetimidate (39 μl neat) was added and the reagents allowed to mix for 5 minutes. Camphorsulfonic acid (3.7 mg) was added and the mixture stirred at room temperature. After 4.5 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×5 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate: hexane (1:2)+1% methanol) gave the title compound (20 mg). MAS: (FAB) 878 (M+Li). Partial 1H NMR δ: 7.38(brs, 1H); 6.30(m, 3H); 5.32M, 5.19m(brd J=3 Hz, 1H); 4.83m, 4.21 M(brs, 1H); 4.62(dd J=15Hz, 2H); 4.41(brd J=14 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1([O:20][C:21]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=O)C=CC=CC=1>>[Br:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:21]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:20])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)COC(=O)Oc1ccccc1
Reactant: Brc1ccc(N2CCNCC2)cn1
Product: CCOC(=O)COC(=O)N1CCN(c2ccc(Br)nc2)CC1

Procedure:
The process is performed as described in Example 1 (step 1.2.). Starting with 3.57 g (14.76 mmol) of 1-(6-bromo-3-pyridyl)piperazine, obtained in step 7.3., and 3.97 g (17.71 mmol) of ethyl [(phenyloxycarbonyl)oxy]acetate, prepared in step 1.1. of Example 1, and after chromatography on silica gel, eluting with a 99/1 and then 98/2 mixture of dichloromethane and methanol, 3.75 g of product are obtained in the form of a yellow oil that crystallizes at room temperature.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]2[N:9]=[CH:10][N:11]([C@@H:12]3[O:32][C@H:31]([CH2:33][O:34]CC4C=CC=CC=4)[C@@H:22]([O:23]CC4C=CC=CC=4)[C@@H:13]3[O:14]CC3C=CC=CC=3)[C:4]=2[CH:3]=1.COC(O)C.[H][H]>[Pd].C(O)(=O)C>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]2[N:9]=[CH:10][N:11]([C@@H:12]3[O:32][C@H:31]([CH2:33][OH:34])[C@@H:22]([OH:23])[C@@H:13]3[OH:14])[C:4]=2[CH:3]=1
Reactant: [H][H]
Reactant: Nc1cc2c(ncn2[C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)c(=O)[nH]1
Agent: [Pd]
Agent: COC(C)O
Solvent: CC(=O)O
Product: Nc1cc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)[nH]1
Yield: 83.5 %

Procedure:
A mixture of 7.5 g of 6-amino-1-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-1,5-dihydro-4H-imidazo[4,5-c]-pyridin-4-one, 1.5 g of 20% palladium on carbon, 6.4 ml of acetic acid, and 150 ml of methoxy-ethanol is hydrogenated at 50° C. and ca 3 atmospheres until uptake of hydrogen ceases. The mixture is filtered, evaporated in vacuo, dissolved in water, and treated with 50 ml of wet IR-45 ion exchange resin. The filtrate is concentrated to dryness in vacuo and recrystallized from ethanol-water to provide 3.2 g of 6-amino-1-β-D-arabinofuranosyl-1,5-dihydro-4H-imidazo[4,5-c]pyridin-4-one.
Reaction SMILES: [BH4-].[Na+].C([O:5][C:6]([C:8]1[N:9]=[N:10][N:11]([CH2:19][C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)[C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O)C.Cl.C(Cl)Cl>CCO>[F:33][C:30]([F:31])([F:32])[C:22]1[CH:21]=[C:20]([CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=1)[CH2:19][N:11]1[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:8]([CH2:6][OH:5])[N:9]=[N:10]1
Reactant: CCOC(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: OCc1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Add sodium borohydride (1.70 g, 0.045 mol) to a solution of 1-(3,5-bis-trifluoromethylbenzyl)-5-phenyl-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester (5.0 g, 0.011 mol) in EtOH (70 mL) and heat the mixture to reflux. After 2 h, cool to RT and add the reaction mixture to 0.5 N HCl (200 mL) and methylene chloride (200 mL). Separate the layers and extract the aqueous layer with methylene chloride (50 mL). Dry the combined organic layers over MgSO4, filter, and concentrate to give [1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-methanol.
Reaction SMILES: [NH2:1][C:2]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[BrH:14].OO>>[NH2:1][C:2]1[C:12]([CH3:13])=[CH:11][C:10]([Br:14])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: Br
Reactant: CCOC(=O)c1cccc(C)c1N
Agent: OO
Product: CCOC(=O)c1cc(Br)cc(C)c1N
Yield: 89.1 %

Procedure:
The above-described method (Example 1) was repeated to react 2-ethyl 2-amino-3-methylbenzoate (16.29 g, 90.0 mmol) with hydrogen bromide (15.93 g, 94.5 mmol, 48% in water) and hydrogen peroxide (11.25 g, 99.0 mmol, 30% in water) and, following working up similar to Example 1, ethyl 2-amino-5-bromo-3-methylbenzoate (20.7 g, 89.1% of theory, >99 area % LC) was obtained as a brown oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ncccc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cnc2[nH]cc(C3CCNCC3)c2c1
Yield: 151.2 %

Procedure:
4-(1H-Pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (963 mg, 3.2 mmol) was set stirring in 1:1 TFA/CH2Cl2. After 45 min the mixture was evaporated and the golden oil brought up in Et2O. A solid formed and was filtered, washed with Et2O and air dried to give 974 mg (96%) of a white solid as a TFA salt. MS (electrospray): exact mass calculated for C12H15N3, 201.13; m/z found, 202.1 [M++H]. 1H NMR (CDCl3, 400 MHz): 8.09 (dd, J=3.33 Hz, 1.57 Hz, 1H), 7.89 (dd, J=6.26 Hz, 1.57 Hz, 1H), 7.01 (s, 1H), 6.99 (dd, J=4.89 Hz, 3.13 Hz, 1H), 5.04 (br s, 2H), 3.11-3.04 (m, 2H), 2.88-2.79 (m, 1H), 2.73-2.64 (m, 2H), 1.94 (d, J=12.52 Hz, 2H), 1.65-1.63 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25](O[C@@H]1[C@@H](OC(=O)C)[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1[N-]C(NC(OC(C)(C)C)=O)CCCCCCCCCCC)(=O)[CH3:26]>C(Cl)(Cl)Cl.CO>[OH:12][CH2:10][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCCCCCCCCCC([N-][C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O)NC(=O)OC(C)(C)C
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCC(CO)NC(=O)OC(C)(C)C
Yield: 82 %

Procedure:
Procedure as for 44, Method C (using 42 in place of 41). RF=0.72 chloroform:methanol 10:0.7 (v/v); yield 82%; 1H NMR δ 3.69-3.45 (m, 2H, αCH, CH2a), 2.97 (m, 1H, CH2b), 1.41 (s, 9H, 3×Boc CH3), 1.25 (m, 18H, 13CH2), 0.88 (t, 3H, CH3); FAB MS C21H43NO3 (357.32) m/z (%) 380 [M+Na]+ (15), 258 [M−Boc+H]+ (100).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40]([C:43]2([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)=[N:41][CH:42]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:38]=[CH:39][C:40]([C:43]4([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[N:41][CH:42]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: NC(=O)C1(c2ccc(Br)cn2)CCOCC1
Product: C[C@@H](c1ccc(-c2ccc(C3(C(N)=O)CCOCC3)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 97 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 4-(5-bromo-pyridin-2-yl)-tetrahydro-pyran-4-carboxylic acid amide following a procedure analogous to that described in Example 1. Yield: 97% of theory; LC (method 1): tR=1.81 min; Mass spectrum (ESI+): m/z=558 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.[CH2:28]([O:30][C:31](=[O:34])[NH:32][CH3:33])[CH3:29]>>[CH2:28]([O:30][C:31](=[O:34])[NH:32][CH2:33][C:24]1[CH:25]=[CH:26][C:21]([C:19]([N:16]2[CH2:17][CH2:18][N:13]([C:5]3[C:4]([CH:1]4[CH2:3][CH2:2]4)=[CH:9][C:8]([CH:10]4[CH2:11][CH2:12]4)=[CH:7][N:6]=3)[CH2:14][CH2:15]2)=[O:20])=[CH:22][CH:23]=1)[CH3:29]
Reactant: O=C(c1ccc(I)cc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: CCOC(=O)NC
Product: CCOC(=O)NCc1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C3CC3)CC2)cc1

Procedure:
Using [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (473 mg) described in Preparation Example 186 and methylcarbamic acid ethyl ester (152 μL) and by the reaction and treatment in the same manner as in Example 262, the title compound (203 mg) was obtained.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([CH:26]([CH3:28])[CH3:27])[CH2:11][C@H:12]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13]C(OC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+].C[OH:32]>O1CCCC1>[CH2:1]([O:8][CH2:9][C@H:10]([CH:26]([CH3:28])[CH3:27])[CH2:11][C@H:12]([NH:18][C:19](=[O:20])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:13][OH:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: COC(=O)C[C@H](C[C@H](COCc1ccccc1)C(C)C)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)[C@@H](COCc1ccccc1)C[C@@H](CO)NC(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
The stirred solution of 5.0 g of methyl 4(S)-benzyloxymethyl-2(S)-tert-butoxycarbonylamino-5-methylhexanecarboxylate [CAS 180182-92-7] in 80 ml of tetrahydrofuran is admixed in portions with 0.660 g of lithium borohydride. The reaction mixture is stirred for another 3 hours, admixed cautiously with 25 ml of methanol and concentrated by evaporation at 40° C. The residue is dissolved once more in 70 ml of methanol and again concentrated by evaporation at 40° C. The residue is admixed with 1M HCl (cold) and extracted with dichloromethane (3×). The combined organic phases are washed with water, dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a colourless oil. Rf=0.32 (1:1 EtOAc-heptane); Rt=4.86 (gradient I).
Reaction SMILES: CC(C)([O-])C.[K+].[N+:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])#[C-:8].[Br:14][C:15]1[CH:16]=[CH:17][C:18]([Cl:25])=[C:19]([CH2:21][C:22](Cl)=[O:23])[CH:20]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([Cl:25])=[C:19]([CH2:21][C:22]2[O:23][CH:8]=[N:7][C:9]=2[C:10]([O:12][CH3:13])=[O:11])[CH:20]=1
Reactant: [C-]#[N+]CC(=O)OC
Reactant: O=C(Cl)Cc1cc(Br)ccc1Cl
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1ncoc1Cc1cc(Br)ccc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of potassium t-butoxide (1.35 g) in tetrahydrofuran (20 ml) was cooled to 0° C., and thereto was added methyl isocyanoacetate (1.33 ml). Then, a solution of the above 5-bromo-2-chlorophenylacetyl chloride in tetrahydrofuran (20 ml) was added thereto, and the mixture was stirred at 0° C. for 2 hours, and then at room temperature overnight. The mixture was cooled again to 0° C. 10% aqueous citric acid solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give 5-bromo-2-chloro-1-(4-methoxycarbonyl-5-oxazolylmethyl)benzene (1.12 g) as a yellow solid. APCI-Mass m/Z 330/332 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([N:15]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:16](=[O:19])[CH2:17][CH3:18])[C:12]([C:24]#[N:25])=[CH:11][C:10]=1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1.[H-].[Na+]>>[NH2:25][C:24]1[C:12]2[C:13](=[N:14][C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[C:10]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH:11]=2)[N:15]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:16](=[O:19])[C:17]=1[CH3:18]
Reactant: CCC(=O)N(CC(C)C)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Agent: [H-]
Agent: [Na+]
Product: Cc1c(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(CC(C)C)c1=O

Procedure:
Using the general procedure of EXAMPLE 40 the product of Step A was treated with NaH to afford the title compound. HPLC/MS: 486.2(M+1), 488.2 (M+3); Rt=4.56 min.
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41]Br)=[CH:37][N:36]=1>CN(C=O)C>[C:32]([C:29]1[CH:28]=[CH:27][C:26]([CH2:25][C:23]2[N:22]([CH2:41][C:38]3[CH:39]=[CH:40][C:35]([Br:34])=[N:36][CH:37]=3)[CH:21]=[N:20][CH:24]=2)=[CH:31][CH:30]=1)#[N:33]
Reactant: BrCc1ccc(Br)nc1
Reactant: N#Cc1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cc2cncn2Cc2ccc(Br)nc2)cc1
Temperature: 100 °C

Procedure:
To a flask was charged 1-trityl -4-p-cyanobenzyl imidazole (2.77 mmol, 1.18 g) from Step 1 and 2-bromo-5-bromomethyl pyridine (2.77 mmol, 0.67 g) from Step 2 in DMF (10 mL) and the mixture heated at 100° C. for 6 hr. The DMF was then removed in vacuo and the residue was triturated with ethyl ether. The ethyl ether was then decanted off and replaced with methanol (20 mL). This solution was then refluxed for 4 hr, cooled to ambient temperature and purified on a C18 preperative hplc column to provide the title compound. High resolution FAB-MS: calc; 353.040183 found; 353.040183. 1H-NMR (CD3OD): 4.2 ppm (s, 2H); 5.4 ppm (s, 2H); 7.2 and 7.6 ppm (d, 2H); 8.1 ppm (s, 1H); 9.1 ppm (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:14])([CH3:13])[C:11](=N)[N:10]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=3)[C:9]2=[S:28])=[CH:4][CH:3]=1.C[OH:30].O>Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])([CH3:14])[C:11](=[O:30])[N:10]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:25])([F:26])[F:27])[CH:17]=3)[C:9]2=[S:28])=[CH:6][CH:7]=1
Reactant: CC1(C)C(=N)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(O)cc1
Reactant: CO
Agent: Cl
Solvent: O
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(O)cc1
Temperature: 25 °C

Procedure:
A mixture of 3b (0.202 g, 0.5 mmol) in HCl aq., 2N (2 ml) and methanol (5 ml) was heated to reflux for 2 h. After being cooled to room temperature, the reaction mixture was poured into cold water (10 ml) and extracted with ethyl acetate (10 ml). The organic layer was dried over MgSO4, concentrated and chromatographed (dichloromethane/acetone, 9:1) to yield 4-[3-(4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile, 3c, [RD8] (0.198 g, 0.49 mmol, 98%) as a white powder.