Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][CH:10]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)#[N:2].[C:23]1(=O)[CH2:27][CH2:26][CH2:25][CH2:24]1.[BH3-]C#N.[Na+]>CO.CC(O)=O>[C:1]([C:3]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[CH:11][CH:10]=2)[CH2:4][CH2:5][N:6]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:7][CH2:8]1)#[N:2]
Reactant: O=C1CCCC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2(C#N)CCNCC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(C2(C#N)CCN(C3CCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.4 %

Procedure:
Compound 348 (230 mg, 0.77 mmol) was dissolved in 20 mL MeOH and 1 mL HOAc. To the solution was added cyclopentanone (280 μL, 3.08 mmol) and the mixture was stirred at RT for 2.5 hours. Then NaBH3CN (290 mg, 4.62 mmol) was added, and the mixture was stirred at RT for overnight. It was concentrated in vacuo, diluted with EtOAc 150 mL, washed with 1N NaOH and water, dried, concentrated in vacuo to dryness to give crude tert-butyl 4-(4-cyano-1-cyclopentylpiperidin-4-yl)phenylcarbamate (349, 280 mg, 98%). It was treated with 4N HCl in dioxane at RT for 4 hours and concentrated in vacuo to dryness to give 4-(4-aminophenyl)-1-cyclopentylpiperidine-4-carbonitrile hydrochloride (350, 250 mg, quantitative yield).
Reaction SMILES: [Cl:1][C:2]1[CH:39]=[CH:38][CH:37]=[CH:36][C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](S(C)(=O)=O)=[N:9][C:8]=2[C:7]([C:20]#[N:21])=[C:6]1[N:22]1[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23]1.[OH-:40].[Na+].[Cl-].[NH4+]>C(O)C>[Cl:1][C:2]1[CH:39]=[CH:38][CH:37]=[CH:36][C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10]([OH:40])=[N:9][C:8]=2[C:7]([C:20]#[N:21])=[C:6]1[N:22]1[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23]1
Reactant: Cn1c(S(C)(=O)=O)nc2c(C#N)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n(Cc3ccccc3Cl)c2c1=O
Reactant: [OH-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: Cn1c(O)nc2c(C#N)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n(Cc3ccccc3Cl)c2c1=O
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-cyano-3-methyl-2-(methylsulfonyl)-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (100 mg) in ethanol (1 ml) was added 1N sodium hydroxide (1 ml), and the resulting mixture was stirred at 80° C. for 5 hours. After the reaction solution was allowed to cool, a saturated aqueous ammonium chloride solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain the title compound (81 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:15])([F:14])[F:13])[C:5](Cl)=[O:6].Cl.[FH:17]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:15])([F:14])[F:13])[C:5]([F:17])=[O:6]
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)c(Br)c1
Reactant: F
Agent: Cl
Product: O=C(F)c1ccc(OC(F)(F)F)c(Br)c1
Yield: 88.7 %

Procedure:
100 ml of anhydrous hydrofluoric acid were cooled to -10° C. 420 g of 3-bromo-4-trifluoromethoxy-benzoyl chloride were added dropwise in the course of two hours at -5° to 0° C., with vigorous evolution of hydrogen chloride. After the evolution of hydrogen chloride had ceased, the temperature was allowed to increase and the reaction allowed to go to completion at 20° C. The excess hydrofluoric acid was distilled off. The residue was purified by distillation. 352.8 g (88.7% of theory) of 3-bromo-4-trifluoromethoxybenzoyl fluoride of refractive index nD20 : 1.4760 were obtained. ##STR21##
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=O)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[SH:24][CH2:25][CH2:26][OH:27]>C(Cl)Cl>[OH:27][CH2:26][CH2:25][S:24][C:6](=[O:8])[C:5]([CH3:10])([CH3:9])[C:4]([O:3][CH2:1][CH3:2])=[O:11]
Reactant: CCOC(=O)C(C)(C)C(=O)O
Reactant: OCCS
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)C(=O)SCCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To a solution of 3-ethoxy-2,2-dimethyl-3-oxopropionic acid (30.78 mmol) in anhydrous CH2Cl2 (20 mL) was added portionwise CDI (40.02 mmol). The reaction mixture was stirred at room temperature during 30 minutes. This solution was added dropwise at −40° C.<T<−30° C. to a solution of 2-mercaptoethanol (41.21 mmol) in anhydrous CH2Cl2 (60 mL). The mixture was stirred at −40° C.<T<−30° C. during 2 hours. The reaction mixture was washed with ice-cold water (×3), dried through a phase separator and evaporated in vacuo while keeping the crude mixture below 25° C. The crude was purified by chromatography on a silica gel column (eluent: petroleum ether/EtOAc 95/5 to 50/50) to give the expected compound as a colorless oil in 30% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 1.15 (t, J=7.05 Hz, 3H), 1.38 (s, 6H), 2.94 (t, J=6.59 Hz, 2H), 3.43-3.48 (m, 2H), 4.10 (q, J=7.04 Hz, 2H), 4.96 (t, J=5.44 Hz, 1H); MS (ESI) m/z=243 (MNa+).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[N:7]#CBr.[CH3:10][N:11]1[CH2:16][CH2:15][CH:14]([CH:17]2[C:23]3=[CH:24][CH:25]=[CH:26][N:22]3[CH2:21][C:20]3[CH:27]=[CH:28][CH:29]=[CH:30][C:19]=3[O:18]2)[CH2:13][CH2:12]1>C(Cl)(Cl)Cl>[C:10]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]2[C:23]3=[CH:24][CH:25]=[CH:26][N:22]3[CH2:21][C:20]3[CH:27]=[CH:28][CH:29]=[CH:30][C:19]=3[O:18]2)[CH2:13][CH2:12]1)#[N:7]
Reactant: CN1CCC(C2Oc3ccccc3Cn3cccc32)CC1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: N#CN1CCC(C2Oc3ccccc3Cn3cccc32)CC1
Reaction time: 1 h

Procedure:
Milled K2CO3 (25 g, 0.18 mole) was added to a solution of cyanogen bromide (10.6 g, 0.1 mole) in 100 ml chloroform, and the mixture was heated to reflux and a solution of 11-[(1-methyl)piperidin-4-yl]-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (24 g, 0.085 mole) in 100 ml chloroform was added thereto over a period of one hour.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1.O.[CH3:9][N:10](C=O)[CH3:11]>>[CH3:9][N:10]([CH3:11])[C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1
Reactant: Brc1csc(Br)n1
Reactant: CN(C)C=O
Solvent: O
Product: CN(C)c1nc(Br)cs1
Yield: 89 %

Procedure:
Synthesis of 2-Dimethylamino-4-tremthylstannylthiazole 386 as illustrated in FIG. 53. 2,4-Dibromothiazole (358; 1.0 equiv) was dissolved in DMF (0.1 M) and heated at 150–160° C. for 8 h, upon which completion of the reaction was indicated by TLC. The mixture was poured into water and extracted with ether (2×). Drying (MgSO4) and evaporation of the solvents gave 2-dimethylamino-4-bromothiazole 385, which was isolated after flash column chromatography (silica gel, 5% EtOAc in hexanes) in 89% yield.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[S:16])[NH2:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Br[CH2:18][C:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)=O.C(OCC)C>C1COCC1>[NH:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:16][CH:18]=[C:19]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)[N:15]=2)[CH2:12][CH2:13]1
Reactant: O=C(O)c1ccc(C(=O)CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2csc(C3CCNCC3)n2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-Thiocarbamoyl-piperidine-1-carboxylic acid tert-butyl ester (2.47 mmol) and 4-(2-Bromo-acetyl)-benzoic acid (2.47 mmol) were mixed in THF (12 mL). After stirring at room temperature for 5 minutes the mixture was heated to 80° C. for 2 hours. The volume was reduced to 5 mL and diethylether (5 mL) was added. The mixture was then cooled to −20° C. and filtered. The solid was washed with a small amount of diethylether and dried. m/z=289.1 in MS ES+, which was characterized by hplc and MS and used in the next step without any further purification.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1.BrC1C=NC=C([F:31])C=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[C:21]([F:31])[CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1
Reactant: Fc1cncc(Br)c1
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccn(C)n2)n1
Product: Cc1ccc(Nc2cncc(F)c2)c(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (example 16) in accordance with the general method of example 20 using 3-Bromo-5-fluoropyridine instead of 3-Bromo-4-methylpyridine to yield the final compound as a yellow solid, MS (ISP): m/e=327.1 (M+H+).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15]/[N:16]=[C:17](\[CH3:25])/[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:26]I.Cl>CN(C)C=O.O>[CH3:26][O:3][CH:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15]/[N:16]=[C:17](\[CH3:25])/[C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CI
Reactant: COC(=O)C(O)c1ccccc1O/N=C(\C)c1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(OC)c1ccccc1O/N=C(\C)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 74.4 %

Procedure:
60% oily sodium hydride (0.20 g, 5.0 mmol) was added to a solution of methyl (E)-α-hydroxy-2-(α-methyl-4-chlorobenzylideneaminooxy)phenylacetate (1.59 g, 4.6 mmol) and methyl iodide (1.95 g, 13.7 mmol) in N,N-dimethylformamide (15 ml) with stirring at 0° C. After 45 minutes, water was added, and the mixture was adjusted to pH 1 with 1N hydrochloric acid, extracted with ether, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel (n-hexane/methylene chloride=9/1) to give the desired compound methyl (E)-α-methoxy-2-(α-methyl-4-chlorobenzylideneaminooxy)phenylacetate (1.19 g, 72%) as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[CH:4][N:3]=1.[NH:10]1[CH:14]=[N:13][CH:12]=[N:11]1>CO.ClCCl>[CH2:8]([C:6]1[CH:7]=[C:2]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[N:3]=[CH:4][N:5]=1)[CH3:9]
Reactant: CCc1cc(Cl)ncn1
Reactant: c1nc[nH]n1
Solvent: ClCCl
Solvent: CO
Product: CCc1cc(-n2cncn2)ncn1
Temperature: 120 °C
Yield: 82.2 %

Procedure:
A mixture of 4-chloro-6-ethylpyrimidine (1.42 g, 10 mmol) and 1H-1,2,4-triazole (1.4 g, 20 mmol) was heated to 120° C. with stirring to give a yellow oil, which deposited an orange solid. The mixture was maintained at 120° C. for 0.2 hours, cooled to 70° C. and dissolved in methanol (10 ml). The solution was diluted with dichloromethane (50 ml) and was washed with saturated sodium bicarbonate solution (20 ml). The aqueous phase was extracted with dichloromethane (2×20 ml) and the combined organic layers were dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica by elution with ethyl acetate to give the title compound (1.44 g, 82%) as a yellow solid, m.p. 75-76° C., which was characterised by 1H-N.M.R. spectroscopy.
Reaction SMILES: Cl[C:2]1[C:3](=[O:13])[N:4]([CH2:9][CH2:10][S:11][CH3:12])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([CH3:26])[CH:25]=1)[NH:22][CH2:21][CH2:20]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:22]2[C:23]3[C:19](=[CH:18][C:17]([O:16][CH3:15])=[CH:25][C:24]=3[CH3:26])[CH2:20][CH2:21]2)[C:3](=[O:13])[N:4]([CH2:9][CH2:10][S:11][CH3:12])[CH:5]=1
Reactant: COc1cc(C)c2c(c1)CCN2
Reactant: CSCCn1cc(Cl)nc(Cl)c1=O
Agent: Cl
Product: COc1cc(C)c2c(c1)CCN2c1nc(Cl)cn(CCSC)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[2-(methylthio)ethyl]-2(1H)-pyrazinone and 5-methoxy-7-methylindoline hydrochloride as the starting materials. mp 111–113° C.; 1H NMR (300 MHz, CDCl3): δ 6.80 (s, 1 H), 6.68 (d, J=2.2 Hz, 1 H), 6.59 (d, J=2.2 Hz, 1 H), 4.40 (t, J=7.7 Hz, 2 H), 4.04 (t, J=7.1 Hz, 2 H), 3.79 (s, 3 H), 3.04 (t, J=7.7 Hz, 2 H), 2.89 (t, J=7.2 Hz, 2 H), 2.18 (s, 3 H), 2.06 (s, 3 H); HRMS (CI) calcd for C17H20N3O2SCl (M+): 365.0965; found m/z 365.0967.
Reaction SMILES: [Br-].[C:2]1([CH2:8][CH2:9][CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Br:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[O:46][N:45]=[C:44]([CH3:47])[C:43]=2[CH:48]=O)=[CH:38][CH:37]=1>C1COCC1.Cl>[Br:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]2[O:46][N:45]=[C:44]([CH3:47])[C:43]=2[CH:48]=[CH:10][CH2:9][CH2:8][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:40][CH:41]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: c1ccc(CCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(Br)cc2)c1C=CCCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of (3-phenylpropyl)triphenylphosphonium bromide (0.956 g, 2.07 mmol) in THF (5 mL) at −78° C. was slowly added n-butyllithium (2.5M in hexanes; 0.83 mL, 2.07 mmol), and the mixture was stirred for 15 minutes. 5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde (0.500 g, 1.88 mmol) in THF (3 mL) was added, and the reaction was warmed to 0° C. and stirred for 1 hour. The solution was diluted with 1N aqueous HCl and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, decanted, and concentrated. The residue was purified by silica gel chromatography (0-20% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][C@H:23]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:24][OH:25].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>ClCCl>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([C:19]([NH:22][C@H:23]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:24][OH:25])=[O:21])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2c(OCc3ccccc3)cccn2c1C(=O)O
Reactant: CCCC[C@@H](N)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCC[C@H](CO)NC(=O)c1c(C)nc2c(OCc3ccccc3)cccn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon, 4 g (14.17 mmol) of 8-(benzyloxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid, 1.83 g (15.59 mmol) of (R)-(−)-2-aminohexanol and 7.166 g (70.85 mmol) of 4-methylmorpholine were suspended in 28 ml of dichloromethane. 5 g (15.59 mmol) of TBTU were then added, and the mixture was stirred at room temperature overnight. After 16 h, the mixture was diluted with 200 ml of dichloromethane and washed with 10% strength aqueous citric acid solution, with water and with saturated aqueous sodium chloride solution. The organic phase was concentrated and the residue obtained was purified on a silica gel cartridge (mobile phase dichloromethane:methanol=100:3). Concentration of the product fractions thus gave 3.83 g (71% of theory) of 8-(benzyloxy)-N-[(2R)-1-hydroxyhexan-2-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@H:3]([OH:18])[CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[C:26]([O:30][C:31]([NH:33][C@H:34]([C:38](O)=[O:39])[CH2:35][S:36]C)=[O:32])([CH3:29])([CH3:28])[CH3:27].OC1C2N=NNC=2C=CC=1.C(N1CCOCC1)C.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(OCC)(=O)C>[C:26]([O:30][C:31]([NH:33][C@H:34]([C:38]([NH:1][C@@H:2]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C@H:3]([OH:18])[CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[C:11]([NH:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])=[O:39])[CH2:35][SH:36])=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CSC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCCN1C[C@@H](O)[C@@H](N)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)[C@@H]1CCCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CS)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 39.3 %

Procedure:
A solution of 1.02 g of 1-[3 (S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-2(S)-piperidinecarboxamide and 685 mg of N-(tert.butoxycarbonyl)-S-methyl-L-cysteine in 7 ml of dry tetrahydrofuran was cooled in an ice/salt mixture. 394 mg of hydroxybenzotriazole , 335 mg of N-ethylmorpholine and 661 mg of dicyclohexylcarbodiimide were added and the mixture was stirred for 3 hours. The mixture was diluted with ethyl acetate and filtered. The filtrate was washed with aqueous sodium bicarbonate solution and with sodium chloride solution and then evaporated. The solvent was removed by evaporation and the residue was chromatographed on silica gel using dichloromethane/methanol (96:4) for the elution to give 630 mg of 1-[3(S)-[[N-(tert.butoxycarbonyl)-L-cysteinyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-2(S)-piperidinecarboxamide in the form of a white solid; MS: m/e 565 [M+H]+.
Reaction SMILES: CON(C)[C:4](=[O:21])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:8]=1.[CH3:23][Li]>O1CCCC1.Cl.CO>[CH:16]1([O:15][C:9]2[CH:8]=[C:7](/[CH:6]=[CH:5]/[C:4](=[O:21])[CH3:23])[CH:12]=[CH:11][C:10]=2[O:13][CH3:14])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: [Li]C
Reactant: COc1ccc(C=CC(=O)N(C)OC)cc1OC1CCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(/C=C/C(C)=O)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a stirred solution of N-methoxy-N-methyl-3-(3-cyclopentyloxy-4-methoxyphenyl)prop-2-enamide (1.986 g, 6.50 mmol) in dry tetrahydrofuran (15 ml) at -78° C. was added methyl lithium (1.4M solution in hexanes, 10.20 ml, 14.3 mmol) dropwise over 3 minutes. The resulting solution was stirred for 1 hour at 0° C., after which time the reaction mixture was diluted with 5% HCl in methanol (20 ml) at 0° C., and partitioned between brine (35 ml) and an equal volume of methylene chloride and diethyl ether (100 ml). The organics were dried (Na2SO4) and concentrated in vacuo to give a light yellow oil. The oil was purified by flash chromatography (SiO2 ; ethyl acetate/hexane (35:65)) to afford the title compound as a colorless oil (1.642 g).
Reaction SMILES: [CH3:1][O-].[Na+].[N:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][CH:15]=2)=[N:6][CH:5]=1>CN(C=O)C.CO>[CH3:1][N:14]1[CH:15]=[C:10]([C:7]2[CH:8]=[CH:9][N:4]=[CH:5][N:6]=2)[CH:11]=[CH:12][C:13]1=[O:16]
Reactant: C[O-]
Reactant: O=c1ccc(-c2ccncn2)c[nH]1
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccncn2)ccc1=O
Temperature: 60 °C

Procedure:
A solution of 4.8 g of sodium methoxide in 300 ml of dry DMF and 15 ml of methanol is added to a suspension of 5-(4-pyrimidinyl)-2(1H)-pyridone (2 g) in 200 ml DMF. The reaction mixture is filtered and 5.5 ml of methyl iodide added to the filtrate. The reaction mixture is heated to 60° C. for 2 hours, cooled to RT, and the solvent evaporated in vacuo leaving a liquid residue that crystallizes upon the addition of distilled H2O. The crystalline solid is stirred with 400 ml of distilled H2O, filtered, washed with H2O, isopropyl alcohol, and ether and then air dried to yield the desired 1-methyl-5-(4-pyrimidyl)-2-pyridone, M.P. 147°-149° C.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][NH:4][CH2:5][C:6]([CH3:16])([N:8]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[N:10]=[CH:9]1)[CH3:7].[CH2:19]=O>C(O)=O>[CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][N:4]([CH3:19])[CH2:5][C:6]([CH3:16])([N:8]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[N:10]=[CH:9]1)[CH3:7]
Reactant: C=O
Reactant: CC(C)(C)CNCC(C)(C)n1cnc([N+](=O)[O-])c1
Solvent: O=CO
Product: CN(CC(C)(C)C)CC(C)(C)n1cnc([N+](=O)[O-])c1

Procedure:
(2,2-Dimethyl-propyl)-[2-methyl-2-(4-nitro-imidazol-1-yl)-propyl]-amine was treated with formalin and formic acid at 85° C. for 5 h, quenched with aqueous sodium bicarbonate, extracted with methylene chloride, dried, concentrated, and the resultant residue purified by chromatography to afford the title compound: H1 NMR (400 MHz, CDCl3) 0.74 (s, 9H), 1.52 (s, 6H), 2.2 (s, 2H), 2.8 (s, 2H), 7.6 (s, 1H), 7.9 (s, 1H); MS m/z 255.3 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([OH:16])[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>>[C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([O:16][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[CH2:12]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(O)C2
Product: CC(C)(C)OC(=O)N1C2CCC1CC(Oc1ccc([N+](=O)[O-])cc1)C2

Procedure:
3-Hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester was reacted with 1-fluoro-4-nitrobenzene by method D. The product with the molecular weight of 348.40 (C18H24N2O5) was obtained in this way; MS (ESI): 349 (M+H+)
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[CH3:33][N:34]1[CH2:39][CH2:38][CH:37]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH2:36][CH2:35]1.[CH2:46]([C:48]1[CH:49]=[C:50]([CH2:56][CH:57]([NH:61][C:62]([N:64]2[CH2:69][CH2:68][CH:67]([N:70]3[CH2:79][C:78]4[C:73](=[CH:74][CH:75]=[CH:76][CH:77]=4)[NH:72][C:71]3=[O:80])[CH2:66][CH2:65]2)=[O:63])[C:58](O)=[O:59])[CH:51]=[CH:52][C:53]=1[CH2:54][CH3:55])[CH3:47]>C1COCC1.C(N(CC)CC)C>[CH2:46]([C:48]1[CH:49]=[C:50]([CH:51]=[CH:52][C:53]=1[CH2:54][CH3:55])[CH2:56][CH:57]([NH:61][C:62]([N:64]1[CH2:69][CH2:68][CH:67]([N:70]2[CH2:79][C:78]3[C:73](=[CH:74][CH:75]=[CH:76][CH:77]=3)[NH:72][C:71]2=[O:80])[CH2:66][CH2:65]1)=[O:63])[C:58]([N:43]1[CH2:44][CH2:45][N:40]([CH:37]2[CH2:36][CH2:35][N:34]([CH3:33])[CH2:39][CH2:38]2)[CH2:41][CH2:42]1)=[O:59])[CH3:47]
Reactant: CN1CCC(N2CCNCC2)CC1
Reactant: CCc1ccc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1ccc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCN(C)CC3)CC2)cc1CC
Temperature: 40 °C
Reaction time: 2 h

Procedure:
336 mg (1.05 mmol) of TBTU, 161 mg (1.05 mmol) of HOBt, 1.02 mL triethylamine and 326 mg (1.05 mmol) of 1-(1-methyl-piperidin-4-yl)-piperazine (used as the tris-hydrochloride) were added to a solution of 500 mg (1.05 mmol) of 3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid in 100 mL of THF, stirred for 4 h at RT and 2 h at 40° C. The solvent was removed in vacuo, the residue was stirred with 40 mL of saturated NaHCO3 solution, the precipitated product was suction filtered, taken up in MeOH and purified by chromatography over silica gel (MeOH). The product fractions were evaporated down, the residue triturated with diethyl ether, suction filtered, washed twice with diethyl ether and dried.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.C[O-].[Na+].[Cl:8][C:9]1[N:14]=[C:13](Cl)[CH:12]=[C:11]([CH2:16][O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)[N:10]=1>C(#N)C>[N:1]1([C:13]2[CH:12]=[C:11]([CH2:16][O:17][CH2:18][CH:19]3[CH2:20][CH2:21]3)[N:10]=[C:9]([Cl:8])[N:14]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C1CNC1
Reactant: Clc1cc(COCC2CC2)nc(Cl)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Product: Clc1nc(COCC2CC2)cc(N2CCC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.5 %

Procedure:
To a mixture of azetidine (93 mg, 0.99 mmol) and sodium methoxide (30 wt % in methanol, 0.135 mL, 0.73 mmol) in acetonitrile (6 mL) was added 2,4-dichloro-6-((cyclopropylmethoxy)-methyl)pyrimidine (77 mg, 0.33 mmol). The reaction was stirred at rt for 30 minutes. The mixture was purified by preparative HPLC to give the title compound (44 mg, 53%).