Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][CH2:13][CH:14]([NH2:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:7][CH2:6]1)([CH3:4])[CH3:3].[Cl:22][C:23]1[C:31]2[C:26](=[CH:27][C:28]([C:32](O)=[O:33])=[CH:29][CH:30]=2)[NH:25][CH:24]=1>>[Cl:22][C:23]1[C:31]2[C:26](=[CH:27][C:28]([C:32]([NH:21][CH:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:13][CH2:12][CH2:11][CH:8]3[CH2:7][CH2:6][N:5]([CH:2]([CH3:4])[CH3:3])[CH2:10][CH2:9]3)=[O:33])=[CH:29][CH:30]=2)[NH:25][CH:24]=1
Reactant: CC(C)N1CCC(CCCC(N)c2ccccc2)CC1
Reactant: O=C(O)c1ccc2c(Cl)c[nH]c2c1
Agent: Cl
Product: CC(C)N1CCC(CCCC(NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccccc2)CC1

Procedure:
Using coupling method A, crude 4-(1-isopropylpiperidin-4-yl)-1-phenylbutylamine hydrochloride (0.70 mmol) and 3-chloroindole-6-carboxylic acid (162 mg, 0.83 mmol) afforded, after purification (SiO2: 10:10:1 hexane:EtOAc:isopropylamine), 66 mg (13%) of the title compound.
Reaction SMILES: [CH3:1][CH:2](C[AlH]CC(C)C)[CH3:3].[Cl:10][C:11]1[CH:12]=[C:13]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22]([O:24]CC)=O)[CH2:17][CH2:16]1>C1(C)C=CC=CC=1>[Cl:10][C:11]1[CH:12]=[C:13]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:14][N:15]1[CH2:16][CH2:17][CH:18]([CH2:21][CH:22]([OH:24])[CH:2]([CH3:3])[CH3:1])[CH2:19][CH2:20]1
Reactant: CC(C)C[AlH]CC(C)C
Reactant: CCOC(=O)CC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Solvent: Cc1ccccc1
Product: CC(C)C(O)CC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.2 %

Procedure:
DIBAL-H (6.9 ml, 10.35 mmol, 1.5 M in toluene) was added to a solution of ethyl [1-(3,4-dichlorobenzyl)piperidin-4-yl]acetate (1.9 g, 5.8 mmol) in dry toluene (60 ml) at −60° C. under nitrogen atmosphere. The reaction mixture was stirred at dry ice bath temperature for 0.5 h, quenched with saturated sodium bisulfite solution and then allowed to warm to room temperature. The aqueous layer was separated and basified with 2N sodium hydroxide to pH between 8-9 and the product was extracted with diethyl ether. The combined ether layers were washed with brine and dried over sodium sulfate. After concentration, the residue was dissolved in dry tetrahydrofuran (30 ml) and cooled to 0° C. Isopropyl magnesium chloride (2.0 M, 5.8 ml) was added dropwise and the resulting reaction mixture was allowed to warm to room temperature. After 0.5 h, the reaction mixture was quenched with water and extracted with diethyl ether. The ether layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified on silica gel column with 25% acetone, 25% dichloromethane in hexanes to give 1(RS)-[1-(3,4-dichlorobenzyl)piperidin-4-ylmethyl]-2-methylpropanol (0.75 g) as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([NH2:11])=[N:9][N:10]=[C:4]2[CH:3]=1.[CH:12]1([NH:15][C:16](=[O:33])[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19](B3OC(C)(C)C(C)(C)O3)[CH:18]=2)[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO>[NH2:11][C:8]1[N:5]2[CH:6]=[CH:7][C:2]([C:19]3[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=3[CH3:23])[C:16]([NH:15][CH:12]3[CH2:13][CH2:14]3)=[O:33])=[CH:3][C:4]2=[N:10][N:9]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Nc1nnc2cc(Br)ccn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccn2c(N)nnc2c1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
A mixture of 7-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-amine (0.202 g, 0.95 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.358 g, 1.2 mmol), sodium carbonate (0.439 g, 4.1 mmol) and trans-dichlorobis(triphenyl-phosphine)palladium (II) (0.057 g, 0.081 mmol) in 7 μL of DME/3 mL of H2O/2 mL of EtOH was heated at 80° C. After 2.5 h, the reaction mixture was cooled to 25° C., evaporated onto silica gel and purified by flash column chromatography eluting with 2M NH3 in MeOH:CH2Cl2 (0:1→3:97) to give the title compound as a tan amorphous solid. MS m/z: 308.1 [M+1].
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[C:6]([N:11]=1)=[N:7][CH:8]=[CH:9][CH:10]=2.[H-].[Na+].[CH3:14]I>CN(C)C=O>[OH:1][CH2:2][C:3]1[N:4]([CH3:14])[C:5]2[C:6]([N:11]=1)=[N:7][CH:8]=[CH:9][CH:10]=2
Reactant: OCc1nc2ncccc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(CO)nc2ncccc21

Procedure:
A procedure similar to that described in Preparation 15 was repeated, except that 45 g of 2-hydroxymethyl-1H-imidazo[4,5-b]pyridine, 13.17 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 20.7 ml of methyl iodide and 1.43 liter of dimethylformamide were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol in ratios ranging from 1:0 to 1:1 by volume as the eluent, to give 3.24 g of the title compound, melting at 130-132° C.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[F:33][C:34]1[CH:35]=[C:36]([CH:64]=[CH:65][C:66]=1[C:67]([F:70])([F:69])[F:68])[C:37]([NH:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:54]=[C:53]3[C:49]([CH2:50][N:51]([C@@H:56]([CH:61]([CH3:63])[CH3:62])[C:57]([O:59]C)=[O:58])[C:52]3=[O:55])=[CH:48][CH:47]=2)=[CH:42][CH:41]=1)=[O:38]>>[F:33][C:34]1[CH:35]=[C:36]([CH:64]=[CH:65][C:66]=1[C:67]([F:70])([F:68])[F:69])[C:37]([NH:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:54]=[C:53]3[C:49]([CH2:50][N:51]([C@@H:56]([CH:61]([CH3:63])[CH3:62])[C:57]([OH:59])=[O:58])[C:52]3=[O:55])=[CH:48][CH:47]=2)=[CH:42][CH:41]=1)=[O:38]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)c(F)c4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)c(F)c4)cc3)cc2C1=O
Yield: 78 %

Procedure:
The compound of example 196 was prepared analogous to compound of example 98 by hydrolysis of compound of example 195.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2O.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:5]1[CH:6]=[CH:7][N:8]=[C:9]2[C:4]=1[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]2
Reactant: Cc1ccc2nccc(O)c2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccc2nccc(Cl)c2n1
Temperature: 25 °C
Yield: 67 %

Procedure:
The suspension of 6-methyl-[1,5]naphthyridin-4-ol (1.60 g, 9.99 mmol) in POCl3 (25 mL) was heated under refluxing for 2 hrs. After cooling to room temperature, the reaction mixture was quenched with ice water and basified with NH4OH followed by extraction with AcOEt. The organic layer was washed with brine and dried over NaSO4, and concentrated to give 8-chloro-2-methyl-[1,5]naphthyridine as a brown solid (1.2 g, 67%). HR-MS-EI (+) m/e calcd for C9H7N2Cl (M+) 178.0298. found 178.0297.
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][C:7]2[C:3](=[N:4][O:5][N+:6]=2[O-:10])[CH:2]=1.[N:11]#[C:12][NH2:13]>>[CH:1]1[CH:9]=[CH:8][C:7]2[N+:6]([O-:10])=[N:11][C:12]([NH2:13])=[N+:4]([O-:5])[C:3]=2[CH:2]=1
Reactant: N#CN
Reactant: [O-][n+]1onc2ccccc21
Product: Nc1n[n+]([O-])c2ccccc2[n+]1[O-]

Procedure:
More particularly, benzofuroxan is reacted with a stoichiometric excess of cyanamide in the presence of an organic base in a non-aqueous medium at about room temperature. When the reaction is complete the reaction mixture is treated with an organic acid to give tirapazamine.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(OCC)(=O)C>N1C=CC=CC=1>[C:8]([NH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1)([O:10][CH2:11][CH3:12])=[O:9]
Reactant: Nc1nccs1
Reactant: CCOC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)Nc1nccs1
Reaction time: 24 h
Yield: 43.4 %

Procedure:
To a stirred solution of 15.1 g (151 mmole) of 2-aminothiazole in 200 ml of dry pyridine is added slowly 18.8 g (173 mmole) of ethyl chloroformate. After approximately 1 day, insolubles are removed by filtration and discarded and the filtrate is concentrated at reduced pressure. The resultant gum is dissolved in aqueous ethanol and redried in vacuo to a sticky solid. The crude product is dissolved in a boiling mixture of 100 ml of ethanol and 25 ml of water, clarified by filtration, and allowed to cool. The resultant crystalline solid is collected and washed thoroughly with water, giving 11.3 g (65.6 mmole) of 2-carbethoxyaminothiazole as a tlc-homogeneous (ethyl acetate eluent on silica gel plates) substance. Structure assignment is supported by the nmr spectrum.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:19]2[O:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.C(OCC)(=O)C.[ClH:35]>C(OCC)(=O)C>[ClH:35].[F:27][C:2]([F:1])([F:28])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:19]2[O:18][CH2:17][CH2:16][NH:15][CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2ccccc2C(F)(F)F)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccccc1-c1cccc2c1OCCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
A mixture of tert-butyl 9-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.508 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (4 ml) was stirred for 1 hr at room temperature, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (144 mg, 86.2%) as a solid.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:15])[NH:6][C:7](=[O:14])[N:8]2[CH2:13][CH2:12][CH2:11][S:10][C:9]=12)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][Cl:27]>CN(C)C=O>[Cl:27][CH2:26][CH2:25][CH2:24][CH2:23][N:6]1[C:5](=[O:15])[C:4]([CH:1]([CH3:3])[CH3:2])=[C:9]2[S:10][CH2:11][CH2:12][CH2:13][N:8]2[C:7]1=[O:14]
Reactant: CC(C)c1c2n(c(=O)[nH]c1=O)CCCS2
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1c2n(c(=O)n(CCCCCl)c1=O)CCCS2
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a suspension of 1.81 g (8 mmol) of 9-isopropyl-3,4-dihydro-2H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione and 1.77 g (12.8 mmol) of potassium carbonate in 30 ml of N,N-dimethylformamide, 1.84 ml (16 mmol) of 1-bromo-4-chlorobutane was added at room temperature, followed by stirring at 60° C. for 2 hours and then at 100° C. for 3 hours. After cooling, the reaction mixture was concentrated to dryness. The residue was dissolved in dichloromethane-water; the organic layer was washed with water and dried. The oily substance obtained by distilling off the solvent was purified by column chromatography (eluent, n-hexane/ethyl acetate=5/1→2/1) to yield 2.12 g (83.6%, colorless oily substance) of the desired product. 1H-NMR (CDCl3, 200 MHz) δ 1.28 (6H, d, J=6.8 Hz), 1.77-1.86 (4H, m), 2.15-2.26 (2H, m), 3.08 (2H, t, J=6.8 Hz), 3.13 (1H, quint., J=7.0 Hz), 3.41-3.60 (2H, m), 3.95 (2H, t, J=7.2 Hz), 4.04-4.10 (2H, m); IR (neat) 2956, 1691, 1637, 1560, 1439, 777, 752 cm-1
Reaction SMILES: CO[C:3](=[O:29])[C:4]1[C:5](=[CH:10][C:11]([N:21]([CH3:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=1)[C:6]([O:8]C)=O.[NH3:30]>C(O)CO>[CH3:28][N:21]([C:11]1[CH:10]=[C:5]2[C:6](=[O:8])[NH:30][C:3](=[O:29])[C:4]2=[CH:13][C:12]=1[NH:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1cc(Nc2ccccc2)c(N(C)c2ccccc2)cc1C(=O)OC
Reactant: N
Solvent: OCCO
Product: CN(c1ccccc1)c1cc2c(cc1Nc1ccccc1)C(=O)NC2=O

Procedure:
Analogously to Example 1, 160 mg (0.41 mmol) of 4-(N-methyl-N-phenylamino)-5-anilinophthalic acid dimethyl ester in 12 ml of ethylene glycol are heated at 120° and, with stirring, ammonia gas is passed through the mixture for 18 hours. The reaction mixture is cooled and extracted with ethyl acetate. The ethyl acetate phases are washed in succession three times with water and once with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed on silica gel with hexane/ethyl acetate 1:1 and the product fractions are combined and concentrated by evaporation, yielding the title compound in the form of slightly yellow crystals, FAB-MS: 344 [M+ +H], 1H-NMR (CDCl3): 3.28 (s, 3H).
Reaction SMILES: [CH2:1]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Mg].[CH:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[Cl-].[NH4+]>O1CCCC1.C(Cl)(Cl)(Cl)Cl>[CH2:1]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCC=O
Reactant: CCCCCCCCCc1ccccc1Br
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CCCCCCCCCc1ccccc1C(O)CCCCC
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A third of a solution of 11 g of 2-nonylbromobenzene [cf. EP-OL 0 123 543] in 15 ml of tetrahydrofuran is added to a mixture, stirred under an argon atmosphere, of 1.1 g of magnesium turnings, 8 ml of tetrahydrofuran and 3 drops of carbon tetrachloride, and the whole is heated at the boil, under reflux, for 30 minutes. The remainder of the solution of 2-nonylbromobenzene (cf. EP-OL 0 123 543) is then added dropwise over a period of 35 minutes and the reaction mixture is maintained under reflux for 2 hours. After dilution with 15 ml of tetrahydrofuran, the suspension is cooled to -10° C. and added in portions to a solution, cooled to -70° C., of 4.6 g of hexanal in 12 ml of tetrahydrofuran. After stirring for 1 hour at -70° C., 200 ml of saturated aqueous ammonium chloride solution are added to the reaction mixture, the organic layer is separated off and the aqueous layer is extracted three times with ether. The residue that remains after the combined ethereal extracts have been dried and concentrated by evaporation is purified by chromatography on silica gel with mixtures of petroleum ether with an increasing amount of methylene chloride, yielding the desired 1-(2-nonylphenyl)-1-hexanol in the form of a colourless oil.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([N:22]5[C:29](=[O:30])[CH2:28][C@@H:27]6[NH:31][C@@H:24]([CH2:25][CH2:26]6)[CH2:23]5)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)S(O[CH2:43][C:44]([F:47])([F:46])[F:45])(=O)=O.O>CN(C)C=O>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([N:22]5[C:29](=[O:30])[CH2:28][C@H:27]6[N:31]([CH2:43][C:44]([F:47])([F:46])[F:45])[C@H:24]([CH2:25][CH2:26]6)[CH2:23]5)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C[C@@H]5CC[C@H](CC4=O)N5)cn3)nc2n1C1CCCC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C[C@H]5CC[C@@H](CC4=O)N5CC(F)(F)F)cn3)nc2n1C1CCCC1
Temperature: 80 °C
Yield: 64.1 %

Procedure:
A sample of 7-Cyclopentyl-N,N-dimethyl-2-(5-((1S,6R)-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (60 mg, 0.123 mmol) was combined with 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.035 ml, 0.246 mmol) in dimethylformamide (1 mL) and heated to (80° C.) overnight. The reaction was then poured into water and extracted with ethyl acetate. The aqueous was washed with ethyl acetate. The organics were combined, dried over sodium sulfate, filtered and concentrated which gave a crude material that was purified by silica gel column chromatography which gave 7-cyclopentyl-N,N-dimethyl-2-(5-((1R,6S)-4-oxo-9-(2,2,2-trifluoroethyl)-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (45 mg) in 64% yield. 1H NMR (400 MHz, CDCl3) δ ppm 8.74 (s, 1H), 8.51 (d, J=9.09 Hz, 1H), 8.22 (s, 1H), 8.15 (d, J=2.53 Hz, 1H), 7.52 (dd, J=8.84, 2.78 Hz, 1H), 6.46 (s, 1H), 4.80 (t, J=8.59 Hz, 1H), 4.23 (d, J=13.64 Hz, 1H), 3.47 (m, 3H), 3.16 (s, 6H), 3.06 (m, 3H), 2.83 (dd, J=15.66, 7.07 Hz, 1H), 2.57 (dd, J=12.13, 8.59 Hz, 2H), 2.04 (m, 6H), 1.70 (m, 4H).
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[C:19]([CH2:25][CH3:26])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:27][CH3:28])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:30][C@H:31]([OH:34])[CH2:32][OH:33]>C(O)(C)C.[OH-].[Na+].CC(=O)OCC>[CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH2:30][C@H:31]([OH:34])[CH2:32][OH:33])=[C:19]([CH2:25][CH3:26])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:27][CH3:28])[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1O
Reactant: OC[C@@H](O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OC[C@H](O)CO
Temperature: 60 °C
Reaction time: 15 h
Yield: 99.4 %

Procedure:
A mixture of 4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (250 mg, 659 μmol), (R)-3-chloro-1,2-propanediol (609 mg, 6.59 mmol) in isopropanol (8 mL) and 3 M aq. NaOH (2 mL) is stirred at 60° C. for 15 h. The mixture is diluted with EA and washed with brine, 1 M aq. NaOH and again with brine. The org. extract is dried over Na2SO4, filtered and concentrated. The crude product is purified on prep. TLC plates using DCM containing 10% of methanol to give the title compound (297 mg) as a pale yellow oil; LC-MS**: tR=0.87 min, [M+H]+=454.26.
Reaction SMILES: O.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]2=[O:17])=[C:7]([CH3:18])[CH:6]=1)([O-])=O>CO>[NH2:2][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]2=[O:17])=[C:7]([CH3:18])[CH:6]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1N1CCCCC1=O
Solvent: CO
Solvent: O
Product: Cc1cc(N)ccc1N1CCCCC1=O
Reaction time: 22 h

Procedure:
800 mg of water-moist palladium on activated carbon are added to a solution of 4.00 g (17.1 mmol) of 1-(4-nitro-2-methylphenyl)piperidin-2-one in 150 ml of methanol, and the mixture is hydrogenated at room temperature and atmospheric pressure for 22 hours. The reaction mixture is filtered, and the filtrate is evaporated, giving 1-(4-amino-2-methylphenyl)piperidin-2-one as a colourless solid; ESI 205.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[Si:7](Cl)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].N1C=CN=C1>>[Si:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][NH2:1])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: NCCCCO
Agent: c1c[nH]cn1
Product: CC(C)(C)[Si](C)(C)OCCCCN

Procedure:
In a manner similar to that in Reference Example 1, 4-amino-1-butanol was reacted with tert-butyldimethylsilyl chloride in the presence of imidazole to give 4-(tert-butyldimethylsilyloxy)-1-butylamine.
Reaction SMILES: [NH2:1][OH:2].[C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH3:19])=[C:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:10]=1)#[N:4]>CCO>[OH:2]/[N:1]=[C:3](/[C:5]1[CH:6]=[CH:7][C:8]([CH3:19])=[C:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])[CH:10]=1)\[NH2:4]
Reactant: NO
Reactant: Cc1ccc(C#N)cc1NC(=O)OC(C)(C)C
Solvent: CCO
Product: Cc1ccc(/C(N)=N/O)cc1NC(=O)OC(C)(C)C
Temperature: 50 °C

Procedure:
NH2OH (20 mL, 50% in water) was added to a stirred solution of tert-butyl 5-cyano-2-methylphenylcarbamate (34) (17.5 g, 75.3 mmol) in EtOH (200 mL) and the resulting solution was heated at 50° C. for 10 hours. The solvent was then evaporated and the product was titurated with EtOAc and hexane to obtain a white solid (Z)-tert-butyl 5-(N′-hydroxycarbamimidoyl)-2-methylphenylcarbamate (35) in a quantitative yield which was used without further purification. MS m/z 266.1 (M+1)+.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:19][C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][N:35]=[C:36]=[O:37])[CH:29]=1.CN1CCOCC1>C(Cl)Cl>[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:19][C:20]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[O:21])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12])[CH2:5][CH2:6][N:7]([C:36](=[O:37])[NH:35][CH2:34][C:30]2[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=2)[CH2:8][CH2:9]1)#[N:3]
Reactant: O=C=NCc1cccnc1
Reactant: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CCNCC1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CCN(C(=O)NCc2cccnc2)CC1

Procedure:
The title compound is prepared from morpholine-4-carboxylic acid [1-(4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide hydrochloride and 3-pyridyl-methyl isocyanate in the presence of a tertiary amine base such as N-methylmorpholine in a solvent such as methylene chloride.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[NH:14][C:13]([C:15]([C:51]4[C:56]([CH3:57])=[CH:55][C:54]([CH3:58])=[CH:53][C:52]=4[CH3:59])=[C:16]4[N:50]=[C:19]([C:20]([C:41]5[C:46]([CH3:47])=[CH:45][C:44]([CH3:48])=[CH:43][C:42]=5[CH3:49])=[C:21]5[NH:40][C:24](=[C:25]([C:31]6[C:36]([CH3:37])=[CH:35][C:34]([CH3:38])=[CH:33][C:32]=6[CH3:39])[C:26]6[CH:27]=[CH:28][C:29]=2[N:30]=6)[CH:23]=[CH:22]5)[CH:18]=[CH:17]4)=[CH:12][CH:11]=3)=[CH:5][CH:4]=1.[CH3:60][O:61][P:62]([O:65]C)[O:63][CH3:64]>C1(C)C=CC=CC=1>[CH3:60][O:61][P:62]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[NH:14][C:13]([C:15]([C:51]4[C:56]([CH3:57])=[CH:55][C:54]([CH3:58])=[CH:53][C:52]=4[CH3:59])=[C:16]4[N:50]=[C:19]([C:20]([C:41]5[C:46]([CH3:47])=[CH:45][C:44]([CH3:48])=[CH:43][C:42]=5[CH3:49])=[C:21]5[NH:40][C:24](=[C:25]([C:31]6[C:36]([CH3:37])=[CH:35][C:34]([CH3:38])=[CH:33][C:32]=6[CH3:39])[C:26]6[CH:27]=[CH:28][C:29]=2[N:30]=6)[CH:23]=[CH:22]5)[CH:18]=[CH:17]4)=[CH:12][CH:11]=3)=[CH:5][CH:4]=1)([O:63][CH3:64])=[O:65]
Reactant: Cc1cc(C)c(-c2c3nc(c(-c4c(C)cc(C)cc4C)c4ccc([nH]4)c(-c4c(C)cc(C)cc4C)c4nc(c(-c5ccc(CBr)cc5)c5ccc2[nH]5)C=C4)C=C3)c(C)c1
Reactant: COP(OC)OC
Solvent: Cc1ccccc1
Product: COP(=O)(Cc1ccc(-c2c3nc(c(-c4c(C)cc(C)cc4C)c4ccc([nH]4)c(-c4c(C)cc(C)cc4C)c4nc(c(-c5c(C)cc(C)cc5C)c5ccc2[nH]5)C=C4)C=C3)cc1)OC
Yield: 79 %

Procedure:
A solution of 26 (200 mg, 240 μmol) in trimethylphosphite (2.2 mL) and toluene (5 mL) was heated to 120° C. under argon for 17 h. The reaction mixture was cooled and concentrated under vacuum. The residue was chromatographed [silica, CHCl3→CHCl3/ethyl acetate (95:5)] to afford a purple solid (164 mg, 79%): 1H NMR δ-2.57 (br s, 2H), 1.84-1.85 (m, 18H), 2.62 (s, 9H), 3.50 (d, J=21.6 Hz, 2H), 3.87 (d, J=11.1 Hz, 6H), 7.27 (s, 6H), 7.67 (dd, J1=8.4 Hz, J2=1.8 Hz, 2H), 8.15 (d, J=7.8 Hz, 2H), 8.63 (s, 4H), 8.67 (d, J=4.8 Hz, 2H), 8.75 (d, J=4.8 Hz, 2H); 31P NMR δ 29.50; LDMS obsd 863.2; FABMS obsd 862.4045; calcd 862.4012 (C56H55N4O3P); λabs=421, 514, 547, 593, 649 nm.
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][C:11]3[CH:13]=[CH:14][C:15]([O:17]C)=[CH:16][C:10]=3[O:9][C:8]2=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH+]1C=CC=CC=1.Cl.C(OCC)(=O)C>O>[CH:1]1([N:7]2[CH2:12][C:11]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:10]=3[O:9][C:8]2=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc2c(c1)OC(=O)N(C1CCCCC1)C2
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1Oc2cc(O)ccc2CN1C1CCCCC1
Temperature: 25 °C

Procedure:
A mixture of 66 g of 3-cyclohexyl-7-methoxy-3,4-dihydro-benzo[e][1,3]oxazin-2-one and 200 g of pyridinium HCl are heated without solvent on a metal bath to 220° for 45 minutes whilst stirring. Evolving HCl gas is sucked off. The mixture obtained is cooled to RT, the melt obtained is dissolved in H2O and ethyl acetate and two phases obtained are separated. The aqueous layer obtained is extracted with ethyl acetate and washed with 1N HCl, dried and concentrated in vacuo. The residue obtained is filtered over silica gel and the filtration residue obtained is concentrated. 3-Cyclohexyl-7-hydroxy-3,4-dihydro-benzo[e][1,3]oxazin-2-one is obtained in crystalline form. m.p. 193-196°.