Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH3:27])=[O:25])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH3:27])=[O:25])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-(3-{[(2-methoxy-2-oxoethyl)(methyl)amino]carbonyl)-1,2,4-oxadiazol-5-yl)hexanoate (Preparation 38) (315 mg, 0.70 mmol) in dichloromethane (10 ml) was treated with trifluoroacetic acid (5 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene. The residue was dissolved in ethyl acetate and washed with a saturated aqueous solution of sodium citrate and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure to afford the title compound as an oil (273 mg)
Reaction SMILES: [C:1]([NH:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][B-](F)(F)F)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[N:30]=2)=[O:28])[CH:21]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([NH:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:20]2[N:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:38])[F:37])[N:30]=3)=[O:28])[CH:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)C1CCN(C[B-](F)(F)F)CC1
Reactant: O=C(Nc1cc(Cl)ncn1)c1cccc(C(F)(F)F)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)NC(=O)C1CCN(Cc2cc(NC(=O)c3cccc(C(F)(F)F)n3)ncn2)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of ((4-(tert-butylcarbamoyl)piperidin-1-yl)methyl)trifluoroborate (45 mg, 0.169 mmol) in THF/water 4:1 (3 mL) are added 6-trifluoromethyl-pyridine-2-carboxylic acid (6-chloro-pyrimidin-4-yl)-amide (51.2 mg, 0.169 mmol), palladium (II) acetate, (0.949 mg, 0.00423 mmol,), X-Phos, (2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl) (4.84 mg, 0.0101 mmol) and Cs2CO3, (165 mg, 0.507 mmol). The mixture is purged with argon and is stirred overnight in a sealed tube at 80° C. The mixture is let to cool down. Water (3 mL) and AcOEt (5 mL) are added and the aqueous phase is extracted with AcOEt (10 mL). The organic phase is dried over MgSO4, filtered and evaporated. The residue is purified by prep HPLC E delivering the title compound (27 mg, 30%) as a white powder, LC-MS A: tR=0.74 min; [M+H]+=465.4.
Reaction SMILES: P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].[OH-].[Na+].[CH2:11]([O:13][C:14]([C@:16]1([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][C@@H:17]1[CH:19]=[CH2:20])=[O:15])[CH3:12]>O.CS(C)=O>[CH2:11]([O:13][C:14]([C@@:16]1([NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:18][C@H:17]1[CH:19]=[CH2:20])=[O:15])[CH3:12]
Reactant: C=C[C@H]1C[C@@]1(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)OCC
Temperature: 39 °C
Reaction time: 24.5 h

Procedure:
To an aqueous solution of sodium phosphate buffer (0.1M, 4.25 L, pH 8) housed in a 12 Liter jacked reactor, maintained at 39° C., and stirred at 300 rpm, was added 511 grams of Alcalase 2.4 L (about 425 mL) (Novozymes North America Inc.). When the temperature of the mixture reached 39° C., the pH was adjusted to 8.0 by the addition of 50% NaOH in water. A solution of (1R,2S)/(1S,2R)N-Boc-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester (85 g) in 850 mL of DMSO was then added over a period of 40 minutes. The reaction temperature was maintained at 40° C. for 24.5 hours during which time the pH of the mixture was adjusted to 8.0 at the 1.5 hour and 19.5 hour time points using 50% NaOH in water. After 24.5 hours, the enantio-excess of the ester was determined to be 97.2%, and the reaction was cooled to room temperature (26° C.) and stirred overnight (16 hours) at which time the enantio-excess of the ester was determined to be 100%. The pH of the reaction mixture was then adjusted to 8.5 with 50% NaOH and the resulting mixture was extracted with MTBE (2×2 L). The combined MTBE extract was washed with 5% NaHCO3 (3×100 mL), water (3×100 mL), and then concentrated in vacuo to give the enantiomerically pure (1R,2S)N-Boc-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester as light yellow solid (42.55 g; purity: 97% (210 nm, containing no acid; 100% enantiomeric excess (“ee”).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][C:3]=1[O:14][CH3:15].[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>S(Cl)(Cl)=O.C(OCC)(=O)C>[CH2:16]([N:18]([CH2:19][CH3:20])[C:9](=[O:11])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([I:1])=[C:3]([O:14][CH3:15])[CH:4]=1)([CH3:13])[CH3:12])[CH3:17]
Reactant: COc1cc(C(C)(C)C(=O)O)ccc1I
Reactant: CCNCC
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)C(C)(C)c1ccc(I)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
A solution of 2-(4-iodo-3-methoxy-phenyl)-2-methyl-propionic acid (326 mg, 0.976 mmol, prepared by saponification of ethyl dimethyl-(3-ethoxy-4-iodophenyl)acetate, example 4) in thionyl chloride (5 mL) was heated at reflux for 1 h. It was concentrated to dryness then taken in 5 mL of tetrahydrofuran. Diethylamine (1 mL, 2 mmol, 2M solution in tetrahydrofuran) was added. The reaction mixture was stirred at room temperature overnight. It was diluted with ethyl acetate, washed with brine (1×), dried over anhydrous sodium sulfate and concentrated. Purification of the crude residue by flash column chromatography (silica gel, IntelliFlash 280, eluting with a gradient of 5-95% ethyl acetate in hexanes) gave N,N-diethyl-2-(4-iodo-3-methoxy-phenyl)-isobutyramide (361.4 mg, 95%) as clear oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][C:14]2[CH:21]=[CH:20][C:17]([CH2:18]O)=[CH:16][C:15]=2[N+:22]([O-:24])=[O:23])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:29])=O>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][C:14]2[CH:21]=[CH:20][C:17]([CH2:18][Cl:29])=[CH:16][C:15]=2[N+:22]([O-:24])=[O:23])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cc(CO)ccc1Oc1ccc(OCc2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cc(CCl)ccc1Oc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 4-[4-(benzyloxy)-phenoxy]-3-nitrobenzyl alcohol (9.43 g, 26.9 mmol) in chloroform (60 ml) was added thionyl chloride (2 ml), followed by stirring at room temperature for 6 hours. After allowing to stand overnight, the reaction solution was washed with water and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; hexane - chloroform (1:1)] to give 4-[4-(benzyloxy)-phenoxy]-3-nitrobenzyl chloride (7.63 g).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[C:13]([C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:23][CH2:22]1)=[O:20])=[CH:12]2)C1C=CC=CC=1.CO>[C].[Pd].O1CCCC1>[C:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[N:24]1[CH2:23][CH2:22][N:21]([C:19]([C:13]2[N:14]([CH3:18])[C:15]3[C:11]([CH:12]=2)=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=3)=[O:20])[CH2:26][CH2:25]1)([CH3:36])([CH3:34])[CH3:35]
Reactant: Cn1c(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cc2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cc2cc(O)ccc21
Temperature: 25 °C
Yield: 80 %

Procedure:
A mixture of 5-(benzyloxy)-2-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}-1-methyl-1H-indole obtained in Example 26 (830 mg), palladium carbon (contains 50% H2O, 100 mg), methanol (100 mL), and tetrahydrofuran (50 mL) was stirred at room temperature under hydrogen atmosphere (5 atm). The mixture was filtered and evaporated under reduced pressure to provide the title compound (540 mg, 80%) as a solid.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:17]3[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:16]=3[N:15]=[C:14]2[CH3:23])[CH2:9]1)(C)(C)C.CO.[ClH:27]>O1CCOCC1>[ClH:27].[CH3:23][C:14]1[N:13]([C@H:10]2[CH2:11][CH2:12][C@H:8]([NH2:7])[CH2:9]2)[C:17]2[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:16]=2[N:15]=1
Reactant: Cc1ccc2c(c1)nc(C)n2[C@H]1CC[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)nc(C)n2[C@H]1CC[C@H](N)C1
Reaction time: 0.25 h

Procedure:
The trans-[3-(2,5-dimethyl-benzoimidazol-1-yl)-cyclopentyl]-carbamic acid tert-butyl ester prepared above (320 mg, 0.95 mmol) was dissolved in HCl (4M) in dioxane (5.0 mL) and the solution was stirred for 15 minutes. Solids came out of solution and 1 mL of methanol was added to dissolve the precipitate. Stirring was continued for 60 minutes and the reaction mixture was evaporated to a sticky solid which was stirred with ethyl ether. The resulting solid was filtered to provide trans-3-(2,5-dimethyl-benzoimidazol-1-yl)-cyclopentylamine hydrochloride salt as an off white powder (250 mg). LR-MS calcd for C14H19N3 (m/e) 229.1579, obsd 230.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.C[Mg+].[Br-].[CH2:19](OCC)C>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)([OH:9])[CH3:19])=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(Br)cc1)C1CCCCC1
Reactant: CCOCC
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)(c1ccc(Br)cc1)C1CCCCC1
Temperature: 0 °C

Procedure:
A solution of (4-bromophenyl)(cyclohexyl)methanone (step 63.2) (3.1 g, 11.60 mmol) in THF (30 ml) was immersed in an ice-bath, followed by dropwise addition of MeMgBr (3M) in diethylether (7.74 ml, 23.21 mmol). The yellow reaction solution was stirred in the ice-bath for 1.5 hrs. The reaction mixture was quenched carefully with saturated aqueous NH4Cl solution and taken up in ethyl acetate. The organic phase was separated and washed with brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to obtain the title compound as yellow oil.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]1([CH:11](Br)[CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[CH2:12]([NH:4][CH2:3][CH2:1][OH:2])[CH2:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(Br)c1ccccc1
Reactant: NCCO
Product: OCCNCCc1ccccc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
A mixture of ethanolamine (10 g, 0.162 mol) and 1-phenylethyl bromide (5 g, 0.027 mol) was stirred at 120° C. for 3 h. The reaction mixture was partitioned between water and dichloromethane. Organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography over silica gel using 3% methanol in dichloromethane to afford (2.5 g) of desired product as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17](=O)[C:16]3[C:11](=[CH:12][C:13]([OH:20])=[C:14]([Cl:19])[CH:15]=3)[O:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.O.[NH2:22][NH2:23]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([C:16]3[CH:15]=[C:14]([Cl:19])[C:13]([OH:20])=[CH:12][C:11]=3[OH:10])=[N:22][NH:23][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c(-c2cccc(Br)c2)coc2cc(O)c(Cl)cc12
Reactant: NN
Solvent: CCO
Solvent: O
Product: Oc1cc(O)c(-c2n[nH]cc2-c2cccc(Br)c2)cc1Cl
Yield: 80.8 %

Procedure:
This compounds was synthesised in the same manner as described above. 3-(3-Bromo-phenyl)-6-chloro-7-hydroxy-chromen-4-one (0.25 g, 0.71 mmol), hydrazine hydrate (5 ml), ethanol (10 ml). The quenched solution was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give a yellow oil which was purified by column chromatography to give 4-[4-(3-Bromo-phenyl)-1H-pyrazol-3-yl]-6-chloro-benzene-1,3-diol as a white solid (0.21 g, 80.8%); Rf 0.8 ethyl acetate/hexane (70/30).
Reaction SMILES: C([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22](Cl)=[N:21][CH:20]=[N:19][C:18]=2[CH:17]=[CH:16]1)(=O)C1C=CC=CC=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][C:32]=1[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=1)[NH2:29].CN1CCCC1=O.C(=O)([O-])O.[Na+]>O>[Cl:25][C:26]1[CH:27]=[C:28]([NH:29][C:22]2[C:23]3[N:15]([CH2:14][CH2:13][O:12][CH2:11][CH2:10][OH:9])[CH:16]=[CH:17][C:18]=3[N:19]=[CH:20][N:21]=2)[CH:30]=[CH:31][C:32]=1[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=1
Reactant: Nc1ccc(Oc2cccc(Cl)c2)c(Cl)c1
Reactant: O=C(OCCOCCn1ccc2ncnc(Cl)c21)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: OCCOCCn1ccc2ncnc(Nc3ccc(Oc4cccc(Cl)c4)c(Cl)c3)c21
Temperature: 120 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
A mixture of 2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate (346 mg), 3-chloro-4-(3-chlorophenoxy)aniline (280 mg) and 1-methyl-2-pyrrolidone (3 mL) was stirred at 120° C. for 2 hrs. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent, ethyl acetate:hexane=30:70→100:0). The object fraction was concentrated under reduced pressure. To a solution of the residue (431 mg) in methanol (10 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 4 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was crystallized from ethyl acetate-diethyl ether to give the title compound (312 mg) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11](=[O:13])[N:10]([CH3:14])[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:17][Si:18]([CH3:25])([CH3:24])[CH2:19][CH2:20][O:21][CH2:22]Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:22][O:21][CH2:20][CH2:19][Si:18]([CH3:25])([CH3:24])[CH3:17])[C:11](=[O:13])[N:10]([CH3:14])[N:9]=2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cn1nc(-c2ccc(Br)cc2)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nc(-c2ccc(Br)cc2)n(COCC[Si](C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
To a solution of compound 10b (1.00 g, 3.94 mmol) in DMF (5 mL) was added sodium hydride (200 mg, 5.00 mmol) in portions at 0° C., and the mixture was stirred for 20 min before 2-(trimethylsilyl)ethoxymethyl chloride (730 mg, 4.37 mmol) was added. The reaction mixture was stirred at rt overnight, and was quenched with H2O (50 mL). The resulting mixture was extracted with DCM (2×50 mL). The combined organic layers were dried over Na2SO4, filtered concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/petroleum ether (1:5 v/v) to obtain compound 10c as a yellow solid (600 mg, 40% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C15H22BrN3O2Si: 383.1 (M+H). Found 383.1.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]([C:15]3([C:38]([O:40]CC45CC6CC(CC(C6)C4)C5)=[O:39])[O:19][C:18]4[CH:20]=[CH:21][C:22]([CH2:24][C@H:25]([NH:27][CH2:28][C@@H:29]([C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=5)[OH:30])[CH3:26])=[CH:23][C:17]=4[O:16]3)=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[K+].[Br-]>C(Cl)(Cl)Cl>[C:1]12([CH2:11][O:12][C:13]([C:15]3([C:38]([OH:40])=[O:39])[O:19][C:18]4[CH:20]=[CH:21][C:22]([CH2:24][C@H:25]([NH:27][CH2:28][C@@H:29]([C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=5)[OH:30])[CH3:26])=[CH:23][C:17]=4[O:16]3)=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: C[C@H](Cc1ccc2c(c1)OC(C(=O)OCC13CC4CC(CC(C4)C1)C3)(C(=O)OCC13CC4CC(CC(C4)C1)C3)O2)NC[C@H](O)c1cccc(Cl)c1
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: C[C@H](Cc1ccc2c(c1)OC(C(=O)O)(C(=O)OCC13CC4CC(CC(C4)C1)C3)O2)NC[C@H](O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{(2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-adamantan-1-ylmethyl ester according to the procedure of Example 22 as an off-white solid; 1H NMR (DMSO) δ 1.03-1.09 (m, 3H), 1.44 (s, 6H), 1.45-1.64 (m, 8H), 1.86 (s, 4H), 3.02-3.15 (m, 1H), 3.25-3.55 (m, 2H), 3.70-3.80 (m, 2H), 4.58 (s, 2H), 5.06-5.10 (m, 1H), 6.52-6.65 (m, 1H), 6.79-6.88 (m, 2H), 7.32-7.49 (m, 3H), 7.49 (s, 1H); IR (KBr) 3384 cm-1 (--OH), 1758 cm-1 (C=O), 1651 cm-1 (C=O); MS (ES) m/z 570.3 (MH+); [α]D25 -29° (c, 1.0, CHCl3). Anal. Calcd. for C31H36ClNO7 : C, 65.31; H, 6.37; N, 2.46; Cl, 6.39. Found: C, 64.19; H, 6.20; N, 2.33; Cl, 6.33.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)[N:3]=1.N1(C2C=C[C:24]([CH:25]=[O:26])=CC=2)C=CC=N1>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[CH:24][CH:25]=[O:26])=[CH:10][CH:9]=2)[N:3]=1
Reactant: Cc1ccnc(-c2ccc(C=O)cc2)n1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: Cc1ccnc(-c2ccc(C=CC=O)cc2)n1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(4-methyl-2-pyrimidinyl)benzaldehyde (prepared as described in Reference Example 14) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 225 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:8](=[CH:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12](C(OC(C)(C)C)=O)[N:11]=2)[C:7](=[O:26])[N:6]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:5]=[CH:4][N:3]1[CH2:33][C:34]([N:36]([CH:45]([CH3:47])[CH3:46])[C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)=[O:35].C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[O:1]=[C:2]1[C:8](=[CH:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][N:11]=2)[C:7](=[O:26])[N:6]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:5]=[CH:4][N:3]1[CH2:33][C:34]([N:36]([CH:45]([CH3:47])[CH3:46])[C:37]1[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=1)=[O:35]
Reactant: COc1ccc(N(C(=O)CN2C=CN(c3ccccc3)C(=O)C(=Cc3nn(C(=O)OC(C)(C)C)c4ccccc34)C2=O)C(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1ccc(N(C(=O)CN2C=CN(c3ccccc3)C(=O)C(=Cc3n[nH]c4ccccc34)C2=O)C(C)C)cc1
Reaction time: 6 h
Yield: 94.3 %

Procedure:
The 2-[2,4-dioxo-3-(1-tert-butyloxycarbonyl-1H-indazol-3-ylmethylene)-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-diazepin-1-yl]-N-isopropyl-N-(4-methoxyphenyl)acetamide (170 mg) was dissolved in CHCl3 (10 ml) and TFA (5 ml) was added. The reaction mixture was stirred for 6 hrs and the solvents were removed in vacuo. The crude product was purified by RP HPLC Dynamax (C-8) (10 ml/min (50% Acetonitrile, 50% Water (0.1% TFA), followed by lyophilization, to afford the titled product of Example 1 (135 mg) as a white lyophilate. HPLC Column: Dynamax C-8 2 ml/min., 30-70% Acetonitrile in aqueous TFA (0.1% v/v) over 20 min., Tr=17.1 min. 1H NMR (400 MHz, CDCl3) 7.93 (d, J=8.3 Hz, 1H), 7.59 (m, 2H), 7.11 (m, 2H), 7.31 (m, 6H), 6.93 (m, 2H), 6.00 (s, 2H), 4.92 (sept., J=6.3 Hz, 1H), 4.15 (m, 1H), 3.92 (m, 4H), 3.82 (s, 3H), 1.04 (d, J=6.3 Hz, 6H), MS (FAB) [M+H]+=538.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])O.[Na+].Br[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH2:22][C:23](Cl)=[O:24]>C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[Cl:21][C:19]1[CH:20]=[CH:15][C:16]([CH:22]2[C:23](=[O:24])[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[O:8]2)=[CH:17][CH:18]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1Br
Reactant: Nc1ccccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1Nc2ccccc2OC1c1ccc(Cl)cc1
Yield: 76.9 %

Procedure:
To a solution of 2-aminophenol (13.5 g) in ethyl acetate (150 ml) is added a solution of sodium hydrogen carbonate (15 g) in water (300 ml), and to the mixture is added dropwise a solution of o-bromo-4-chlorophenylacetyl chloride (32.2 g) in toluene with vigorous stirring under ice cooling. After the mixture is stirred at room temperature for one hour, the solvent in the organic layer is distilled off and the residue is dissolved in acetone. To the solution is added potassium carbonate (20 g), and the mixture is stirred at room temperature overnight. The solvent is distilled off and to the residue is added water. The mixture is extracted with ethyl acetate. The ethyl acetate layer is washed, dried and distilled to remove the solvent, and the residue is recrystallized from ethyl acetate-n-hexane to give 2-(4-chlorophenyl)-3-oxo-3,4-dihyro-2H-1,4-benzoxazine (24.0 g) as crystals. M.p. 180.5°-181.5° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH:23]=[N:22][C:21]([C:24]([F:27])([F:26])[F:25])=[N:20]1)=[O:11].Br[C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[CH:23]=[N:22][C:21]([C:24]([F:27])([F:26])[F:25])=[N:20]2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=1
Reactant: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Cc1ccc(Br)nc1
Product: Cc1ccc(NC[C@@H]2[C@H](C)CCCN2C(=O)c2cc(C)ccc2-n2cnc(C(F)(F)F)n2)nc1

Procedure:
The title compound was synthesized following the same general protocol as described in Example A44, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)phenyl)methanone and 2-bromo-5-methylpyridine. ESI-MS (m/z): 473 [M+1]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[C:9](=[O:16])[NH:10][C:11](SC)=[N:12][CH:13]=2)[CH:2]=1.C(SCCN)C1C=CC=CC=1>N1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[C:9](=[O:16])[NH:10][CH:11]=[N:12][CH:13]=2)[CH:2]=1
Reactant: CSc1ncc(Cc2cccnc2)c(=O)[nH]1
Agent: NCCSCc1ccccc1
Solvent: c1ccncc1
Product: O=c1[nH]cncc1Cc1cccnc1

Procedure:
A mixture of 5-(3-pyridylmethyl)-2-methylthio-4-pyrimidone (1.0 g),2-(benzylthio)ethylamine (1.06 g) and dry pyridine (30 ml) was heated under reflux for 40 hours and evaporated to dryness. Water was added to the residue and the mixture was extracted with chloroform (discarded). The aqueous phase was adjusted to pH 7 and was extracted with chloroform. This extract was evaporated to dryness and the residue was recrystallised from ethanol to give 2-[2-benzylthio)ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone m.p. 145°-148°.