Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:21]1[O:22][C:23]2[C:24](=[C:26]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:28][CH:29]=2)[N:25]=1>COCCOC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:21]2[O:22][C:23]3[C:24](=[C:26]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:28][CH:29]=3)[N:25]=2)[C@@H:10]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN[C@@H](C(C)(C)C)C1
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1cccc2oc(N3CCN(C(=O)OC(C)(C)C)C[C@@H]3C(C)(C)C)nc12
Reaction time: 0.75 h
Yield: 39 %

Procedure:
To (S)-4-tert-butyloxycarbonyl-2-tert-butylpiperazine (640 mg, 2.6 0 mmol) in DME (10 mL) at room temperature, was added NaH (60% suspension in mineral oil, 115 mg, 3.50 mmol) and the mixture was stirred for 45 min. Methyl 2-chlorobenzoxazole-4-carboxylate (780 mg, 3.69 mmol) was added to the reaction mixture and the reaction was stirred at room temperature for 3d and at 55° C. for 24 h. The reaction mixture was quenched with CH3OH (10 mL), silica gel (15 mL) was added, and solvent removed under reduced pressure. The residue was purified by column chromatography (silica gel, 33% EtOAc in hexanes) to afford (S)-methyl 2-(4-tert-butyloxycarbonyl-2-tert-butyl-piperazin-1-yl)benzoxazole-4-carboxylate (0.42 g, 39%) as a yellow solid. 1H NMR and MS consistent.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]12[CH2:13][CH2:12][C:9]([C:14]3[NH:22][C:21]4[C:20](=[S:23])[NH:19][C:18](=[O:24])[N:17]([CH2:25][CH2:26][CH3:27])[C:16]=4[N:15]=3)([CH2:10][CH2:11]1)[CH2:8][CH2:7]2.[OH-].[Na+].[CH3:31]CO>O>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]12[CH2:7][CH2:8][C:9]([C:14]3[NH:22][C:21]4[C:20]([S:23][CH3:31])=[N:19][C:18](=[O:24])[N:17]([CH2:25][CH2:26][CH3:27])[C:16]=4[N:15]=3)([CH2:10][CH2:11]1)[CH2:12][CH2:13]2
Reactant: CCO
Reactant: CCCn1c(=O)[nH]c(=S)c2[nH]c(C34CCC(CCC(=O)OC)(CC3)CC4)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCn1c(=O)nc(SC)c2[nH]c(C34CCC(CCC(=O)OC)(CC3)CC4)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-[4-(2-Oxo-3-propyl-6-thioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-propionic acid methyl ester (100 mg) was dissolved in 2 mL of EtOH and 1 mL of H2O. NaOH (20 mg) was added as a solution in 1 mL of H2O, followed by Mel (23 uL, 1.5 eq). The resulting reaction mixture was stirred at rt for 30 min. It was then extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated under reduced pressure to afford 105 mg of the titled compound.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:10][C:9]([CH2:11][CH3:12])=[C:8]([CH:13]=[O:14])[CH:7]=1.[CH:15]1([Mg]Br)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.O1CCCC1.O>O1CCCC1>[CH:15]1([CH:13]([C:8]2[CH:7]=[C:6]([CH:2]3[O:3][CH2:4][CH2:5][O:1]3)[S:10][C:9]=2[CH2:11][CH3:12])[OH:14])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Br[Mg]C1CCCCC1
Reactant: CCc1sc(C2OCCO2)cc1C=O
Solvent: C1CCOC1
Solvent: O
Product: CCc1sc(C2OCCO2)cc1C(O)C1CCCCC1
Reaction time: 1.5 h
Yield: 71 %

Procedure:
To a solution of 5-(1,3-dioxolan-2-yl)-2-ethylthiophene-3-carbaldehyde (6.36 g) synthesized above in tetrahydrofuran (130 mL) was added dropwise 1.0M cyclohexylmagnesium bromide-tetrahydrofuran solution (40 mL) at 0° C., and the mixture was stirred for 1.5 hr under an argon atmosphere. Water was added to quench the reaction, tetrahydrofuran was evaporated using evaporator, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate/hexane) to give the title compound (6.30 g, 71%) as a pale-yellow oil.
Reaction SMILES: CS[C:3]1[S:4][C:5](=[CH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]=[CH:13]3)[C:6](=[O:8])[N:7]=1.[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[C:23]([O:28][CH3:29])[CH:22]=1.CCN(C(C)C)C(C)C>>[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][N:14]=[CH:13]4)/[C:6](=[O:8])[N:7]=2)=[C:23]([O:28][CH3:29])[CH:22]=1
Reactant: COc1cc(F)ccc1N
Reactant: CSC1=NC(=O)C(=Cc2ccc3ncncc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(F)ccc1NC1=NC(=O)/C(=C/c2ccc3ncncc3c2)S1

Procedure:
Similar procedure as described in example 1d was used, starting from 2-methylsulfanyl-5-quinazolin-6-ylmethylene-thiazol-4-one, 4-fluoro-2-methoxy-aniline and DIEA to give 2-(4-fluoro-2-methoxy-phenylamino)-5-[1-quinazolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one: LC-MS m/e observed. LC-MS m/e 381 (MH+).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH3:10][C:11]1[CH:30]=[CH:29][CH:28]=[CH:27][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([NH2:26])=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1>C1COCC1>[CH3:10][C:11]1[CH:30]=[CH:29][CH:28]=[CH:27][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21]3=[N:26][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:22]3[CH:23]=[CH:24][CH:25]=2)=[CH:18][CH:19]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Cc1ccccc1Oc1ccc(-c2cccnc2N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1Oc1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 284 mg) in THF (dry) (15 ml) was added 2-chloroethanesulfonyl chloride (0.448 ml) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(4-(2-methylphenoxy)phenyl)pyridin-2-amine (392 mg) in THF (dry) (20 mL) was added at 0° C. and the mixture was stirred at room temperature for 5 hr. The mixture was quenched with water at 0° C. Water, EtOAc and IPE were added and the precipitates were collected, washed with water/EtOAc, dried in vacuo to give the title compound (415.4 mg) as a white solid. A part of this was recrystallized from MeCN/IPE.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7](=[O:27])[N:8]2[C:12](=[CH:13][C:14]=1[CH:15]([CH2:21][CH3:22])C(OCC)=O)[C:11]1([O:26][CH2:25][CH2:24][O:23]1)[CH2:10][CH2:9]2)(=[O:3])C.O.[OH-].[Li+]>CO>[CH2:21]([CH:15]1[C:14]2[CH:13]=[C:12]3[N:8]([CH2:9][CH2:10][C:11]43[O:23][CH2:24][CH2:25][O:26]4)[C:7](=[O:27])[C:6]=2[CH2:5][O:4][C:1]1=[O:3])[CH3:22]
Reactant: CCOC(=O)C(CC)c1cc2n(c(=O)c1COC(C)=O)CCC21OCCO1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC1C(=O)OCc2c1cc1n(c2=O)CCC12OCCO2
Temperature: 25 °C
Reaction time: 22 h

Procedure:
Dissolved in 15 ml of methanol was 759 mg of ethyl 6-[(acetoxy)methyl]-α-ethyl-1,1-(ethylenedioxy)-5-oxo-1,2,3,5-tetrahydroindolizine-7-acetate (V), followed by an addition of 5 ml of water and a further addition of 420 mg of lithium hydroxide (monohydrate). The resultant mixture was stirred at room temperature for 2 hours. After removal of methanol by distillation, the residue was added first with about 10 ml of ice water and then with 1.5 ml of acetic acid, followed by stirring at room temperature for 22 hours.
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[NH:10][C:9](/[CH:14]=[CH:15]/[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)=[N:8][C:7]=2[N:6]([CH2:24][CH3:25])[C:4]1=[O:5])[CH3:2].[C:26](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[N:10]([CH3:26])[C:9](/[CH:14]=[CH:15]/[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)=[N:8][C:7]=2[N:6]([CH2:24][CH3:25])[C:4]1=[O:5])[CH3:2]
Reactant: CCn1c(=O)c2[nH]c(/C=C/c3cccc(OC)c3)nc2n(CC)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCn1c(=O)c2c(nc(/C=C/c3cccc(OC)c3)n2C)n(CC)c1=O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
Compound r (1.70 g, 5.0 mmol) obtained in Reference Example 17 was dissolved in 40 ml of dimethylformamide. To the solution were added 1.73 g (12.5 mmol) of potassium carbonate and subsequently 0.62 ml (10.0 mmol) of methyl iodide, and the resulting mixture was stirred at 50° C. for 30 minutes. After cooling, insoluble matters were filtered off, and 100 ml of water was added to the filtrate. The mixture was extracted three times with 50 ml of chloroform. The extract was washed twice with water and once with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The obtained crude crystals were purified by silica gel column chromatography (eluent: 40% ethyl acetate/hexane), followed by recrystallization from cyclohexane/toluene to give 1.10 g (yield 62%) of Compound s as pale yellow needles.
Reaction SMILES: [OH-].[Li+].C([O:5][C:6](=[O:38])[CH:7]([S:34]([CH3:37])(=[O:36])=[O:35])[CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][C:13]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])[CH2:12][CH2:11]1)C.Cl>O.O1CCCC1>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([S:24]([C:13]2([C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=3[F:23])[CH2:12][CH2:11][CH:10]([CH2:9][CH2:8][CH:7]([S:34]([CH3:37])(=[O:35])=[O:36])[C:6]([OH:38])=[O:5])[CH2:15][CH2:14]2)(=[O:25])=[O:26])=[CH:28][CH:29]=1
Reactant: CCOC(=O)C(CCC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)C(CCC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1)C(=O)O
Reaction time: 12 h
Yield: 82 %

Procedure:
A solution of lithium hydroxide (21 mg, 0.88 mmol) in water (700 mL) was added to the product from Example 108 (100 mg, 0.18 mmol) in tetrahydrofuran (2 mL). The resulting mixture was stirred vigorously for 12 hours, then poured into 1M aqueous hydrochloric acid (20 mL) and extracted with ethyl acetate (2×40 mL). The combined organic layers were dried (NaSO4), and concentrated. The residue was purified using column chromatography on silica, eluting with 95/5/0.5 dichloromethane/methanol/acetic acid to give the title compound (79 mg).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11](/[CH:23]=[CH:24]/[CH:25]([CH3:28])[C:26]#[N:27])[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[NH:17][S:16]1(=[O:22])=[O:21])C1C=CC=CC=1>CCOC(C)=O.CCO.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][CH:25]([CH3:28])[C:26]#[N:27])[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[NH:17][S:16]1(=[O:22])=[O:21]
Reactant: CC(C#N)/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C#N)CCc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1
Reaction time: 2 h

Procedure:
A mixture of (E)-4-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-2-methyl-but-3-enenitrile (10 mg) and Pd(OH)2 (1 mg) in EtOAc/EtOH (3 mL) is hydrogenated at 1 atm for 2 h. The catalyst is filtered and the filtrate evaporated. The residue is washed with 1N HCl and the residue is purified by preparative HPLC to give the title compound: (M−1)−=308; HPLC retention time=0.78 min (method A).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][C:3]=1[C:10]([Cl:14])=[C:11]([Cl:13])[Cl:12].[N-:15]=[N+:16]=[N-:17].[Na+]>C(O)C>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:15]=[N+:16]=[N-:17])=[CH:4][C:3]=1[C:10]([Cl:14])=[C:11]([Cl:13])[Cl:12]
Reactant: Cc1ccc(CCl)cc1C(Cl)=C(Cl)Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(CN=[N+]=[N-])cc1C(Cl)=C(Cl)Cl
Yield: 89 %

Procedure:
A solution of 4-methyl-3-(trichlorovinyl)benzyl chloride (1.81 g ) and sodium azide (650 mg) in 20 ml of ethanol was heated at reflux for 5 hours. The reaction mixture was concentrated and then chromatographed on silica gel. Elution with 1:1 hexane:methylene chloride afforded 1.65 g of pure azide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10](Br)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[N+:13]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14].CO>C1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:13]([O-:15])=[O:14])[CH:21]=3)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Cc1cc(Br)c2ncccc2c1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Solvent: CO
Solvent: c1ccccc1
Product: Cc1cc(-c2cccc([N+](=O)[O-])c2)c2ncccc2c1
Yield: 98.6 %

Procedure:
To a mixture of 6-methyl-8-bromoquinoline (1.0 g), 3-nitrobenzene boronic acid (0.63 g), purchased from Lancaster Chemicals, 2M NaCO3 (1.9 mL), methanol (6.5 mL) and benzene 32 mL) was added palladium tetrakis triphenylphosphine (0.47 g) and heated to reflux for 6 hours. The progress of the reaction was monitored by thin-layer chromatography. Upon completion, the reaction mixture was cooled and the solvents removed. Ethyl acetate was added to the residue and the solution was filtered through a pad of Na2SO4. The solution was concentrated and the desired product was purified and isolated by preparative thin-layer chromatography yielding 6-methyl-8-(3-nitrophenyl)quinoline (983 mg) as a yellow oil. Characteristic analytical data are: elemental analysis [calculate (found)] C: 72.72 (72.63), H: 4.58 (4.32), and N: 10.60 (10.72).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[CH3:9][C:10]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH2:11].B(F)(F)F.CCOCC>>[CH3:8][C:3]1[CH:4]=[CH:5][C:6]([OH:7])=[C:1]([C:10]([CH3:11])([CH3:9])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:2]=1
Reactant: Cc1ccc(O)cc1
Reactant: C=C(C)CC(C)(C)C
Agent: FB(F)F
Solvent: CCOCC
Product: Cc1ccc(O)c(C(C)(C)CC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 2.67 h

Procedure:
Preparation was modified from the method of Kitchen, L. J., J. Am. Chem. Soc. 1948, 70, 1290. In a round-bottom flask to which were attached two addition funnels, a mixture of p-cresol (33.12 g, 306 mmol) and 33 mL 2,4,4-trimethyl-1-pentene was purged with nitrogen. The flask was cooled to 0° C., and 162 mL additional olefin (total amount of 2,4,4-trimethyl-1-pentene=1.23 mol, 4.0 eq.) was added dropwise, while a mixture of boron trifluoride etherate (5 mL, 40 mmol) and 30 mL nitrogen-sparged hexanes was added at the same time. The addition of olefin proceeded for 160 min, and subsequently the flask was allowed to warm to room temperature, and then was heated to 45° C. with stirring under nitrogen for 16 h. After cooling back to room temperature, the reaction was quenched by the addition of 121 g of 30% NaOH/H2O and 10 mL hexanes. After separation, the organic fraction was washed with water, and the combined aqueous fractions were washed with hexanes. The combined organic fractions were again washed with water and then distilled. The fraction distilling at 141° C. and 9-10 Torr was saved and analyzed. Yield: 30.56 g waxy white solid (45%). M.P.=42-5° C. 1H NMR was in accordance with literature (PCT Int. Appl. WO 2006120178 A1, inventors Olesen, Preben. H.; Hansen, H. C.; Christiansen, L. B.; Nielsen, F. E.; Petersen, A. K., to Novo Nordisk A/S).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)OC(C)C)#[N:2].[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:19][NH2:20]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)=[N:20][CH2:19][C:18]1[CH:21]=[CH:22][C:23]([Cl:24])=[C:16]([Cl:15])[CH:17]=1)#[N:2]
Reactant: CC(C)OC(=NC#N)c1ccncc1
Reactant: NCc1ccc(Cl)c(Cl)c1
Solvent: CO
Product: N#CNC(=NCc1ccc(Cl)c(Cl)c1)c1ccncc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.8 %

Procedure:
Isopropyl N-cyano-4-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 3,4-dichlorobenzylamine (0.52 g, 3.0 mmol) was added. The mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate was crystallized from methanol-diethyl ether to give the title compound (0.42 g, 1.4 mmol, yield: 52%) as colorless crystals.
Reaction SMILES: [N:1]([C@H:4]1[CH2:28][C@@:27]2([CH3:29])[CH:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:30])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6][CH:5]1[OH:31])=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC>O>[NH2:1][C@H:4]1[CH2:28][C@@:27]2([CH3:29])[CH:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:30])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6][CH:5]1[OH:31]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CC(O)[C@@H](N=[N+]=[N-])C[C@]4(C)[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CC(O)[C@@H](N)C[C@]4(C)[C@H]3CC[C@]12C

Procedure:
4 g 2β-azido-cholestane-3-ol and 0.2 g lithium aluminium hydride are stirred in 50 ml abs. ether for one day at room temperature. After careful decomposition with water and repeated ether extraction, the combined ethereal solutions are washed with water, dried over sodium sulfate and the solvent is reduced to 50 ml. Upon introduction of hydrogen chloride, the corresponding hydrochloride crystallizes out in the form of colorless needles which, after recrystallization from acidified methanol, melt at 254-256° C.
Reaction SMILES: [F:1][CH:2]([F:42])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH3:41])=[C:21]([NH:23][C:24]([N:26]4[CH2:33][C:30]5([CH2:32][CH2:31]5)[N:29](CC5C=CC=CC=5)[CH2:28][CH2:27]4)=[O:25])[CH:22]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1.[H][H]>CO.[Pd]>[F:42][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH3:41])=[C:21]([NH:23][C:24]([N:26]4[CH2:33][C:30]5([CH2:32][CH2:31]5)[NH:29][CH2:28][CH2:27]4)=[O:25])[CH:22]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: Cc1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1NC(=O)N1CCN(Cc2ccccc2)C2(CC2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1NC(=O)N1CCNC2(CC2)C1

Procedure:
N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-(phenylmethyl)-4,7-diazaspiro[2.5]octane-7-carboxamide D8a (prepared as described for D1; 0.2 mmol) is dissolved in 10 mL MeOH followed by addition of 5% mol of Pd/C (10% in weight). The flask is charged with a hydrogen balloon for 12 h stiffing. The mixture is filtered over a celite pad and the filtrate is concentrated to afford N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4,7-diazaspiro[2.5]octane-7-carboxamide D8, which is used without further purification. MS (m/z) (M+1)+: 523.1.
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[CH:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>>[Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: CS(=O)c1ncc2cc(Br)c(=O)n(C3CCCC3)c2n1
Reactant: Nc1ccccn1
Product: O=c1c(Br)cc2cnc(Nc3ccccn3)nc2n1C1CCCC1
Yield: 37 %

Procedure:
6-Bromo-8-cyclopentyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one and 2-aminopyridine were reacted according to the procedure outlined in Example 37 to provide 6-bromo-8-cyclopentyl-2-(pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one in 37% yield. mp: 273˜275° C. Anal. Calc'd for C17H16BrN5O.0.1H2O: C, 52.62; H, 4.21; N, 18.05. Found C, 52.23; H, 4.10; N, 17.91. M++1: Calc'd: 386.05, Found 385.9.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:19][N:5]2[C:6](=[O:18])[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C@H:4]2[CH2:3]1.CC(C)([O-])C.[K+].Br[C:27]1[CH:32]=[N:31][C:30]([CH:33]2[CH2:35][CH2:34]2)=[CH:29][N:28]=1.CO>O1CCCC1>[CH:33]1([C:30]2[N:31]=[CH:32][C:27]([O:1][C@@H:2]3[CH2:19][N:5]4[C:6](=[O:18])[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:10][C@H:4]4[CH2:3]3)=[N:28][CH:29]=2)[CH2:35][CH2:34]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)N2C[C@@H](O)C[C@@H]2C1
Reactant: Brc1cnc(C2CC2)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=O)N2C[C@@H](Oc3cnc(C4CC4)cn3)C[C@@H]2C1
Reaction time: 0.08 h
Yield: 52 %

Procedure:
tert-Butyl (8S,9aR)-8-hydroxy-5-oxohexahydro-1H-pyrrolo[1,2-a][1,4]diazepine-2(3H)-carboxylate (55 mg, 0.203 mmol, Part F) was dissolved in tetrahydrofuran (1.2 mL). Potassium tert-butoxide (0.400 mL, 0.400 mmol, 1.0 M in tetrahydrofuran, 2.0 equivalents) was added at room temperature, and the resulting solution was stirred for five minutes. Then 2-bromo-5-cyclopropylpyrazine (81 mg, 0.407 mmol, 2.0 equivalents) was added as a solution in tetrahydrofuran (0.5 mL). The reaction was allowed to stir at room temperature for 16 hours, at which point it was quenched with 3 drops of saturated sodium bicarbonate. The mixture was concentrated in vacuo, and the residue was loaded onto a 12 g silica column eluted with 100:0 to 95:5 dichloromethane:methanol over 20 minutes to give the titled compound (41 mg, 52% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 8.02 (d, J=1.0 Hz, 1H), 7.93 (d, J=1.4 Hz, 1H), 5.44 (t, J=4.0 Hz, 1H), 4.45-4.17 (br s, 2H), 4.07-3.98 (m, 2H), 3.67 (dd, J=13.8, 4.1 Hz, 1H), 3.00 (br s, 1H), 2.73-2.66 (m, 3H), 2.49 (dd, J=12.0, 7.6 Hz, 1H), 2.01-1.82 (m, 2H), 1.48 (s, 9H), 1.02-0.89 (m, 4H); MS (ESI+) m/z 333.0 (M-tBu+H)+.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:22])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1.I[CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH3:9][O:10][C:11](=[O:22])[CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)[CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COC(=O)Cc1cccc([N+](=O)[O-])c1
Reactant: ICC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)C(CC1CCCC1)c1cccc([N+](=O)[O-])c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 46.8 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (43.3 mL of a 0.3M stock solution, 12.99 mmol) cooled to −78° C. was treated with (3-nitro-phenyl)-acetic acid methyl ester (2.45 g, 12.56 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (32 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (2.78 g, 13.23 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.78 mL), and the mixture was stirred at −78° C. for 3 h. The reaction was warmed to 25° C. and was stirred at 25° C. for 16 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (25 mL) and was concentrated in vacuo. The residue was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with a saturated aqueous lithium chloride solution (2×25 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh 80/20 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3-nitro-phenyl)-propionic acid methyl ester (1.63 g, 46.8%) as pale yellow oil: EI-HRMS m/e calcd for C15H19NO4 (M+) 277.1314, found 277.1317.