Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.C([Li])CCC.[CH:12]12[O:18][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17]2>C1COCC1>[CH3:1][N:2]1[C:6]([C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[OH:18])=[CH:5][N:4]=[N:3]1
Reactant: Cn1ccnn1
Reactant: C1CCC2OC2C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nncc1[C@H]1CCCC[C@@H]1O
Yield: 4.5 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 8a by using 1-methyl-1H-1,2,3-triazole (2.00 g, 24.1 mmol), n-butyl lithium (2.69 M solution in hexane; 9.0 mL, 24.2 mmol), cyclohexene oxide (2.40 g, 24.5 mmol) and THF (70 mL), to yield the title compound (197 mg, 4.5%) as a colorless oil.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20].[CH3:34][O:35][CH2:36][C@@H:37](O)[CH3:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:38][C@@H:37]([O:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20])[CH2:36][O:35][CH3:34]
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Reactant: COC[C@H](C)O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC[C@@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 20 h
Yield: 67.2 %

Procedure:
DIAD (4.6 g, 0.029 mol) was added dropwise to a solution of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (6 g, 0.023 mol), (S)-(+)-1-methoxy-2-propanol (2.59 g, 0.029 mol) and triphenylphosphine (7.53 g, 0.029 mol) in THF (100 mL), under argon, at 0° C. The reaction was stirred at 0° C. for 1 hour and at RT for 20 hours. The volatiles were removed in vacuo and isohexane/ethyl acetate 2:1 added followed by stirring for 1 hour. A white solid was removed by filtration and the filtrate was evaporated to a residue which was chromatographed on silica, eluting with a gradient of 0-20% ethyl acetate in isohexane, to give the desired compound (5.11 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:13](Cl)(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(Cl)(Cl)Cl>O>[O:25]=[C:13]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: C1COCCN1
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCCCCCCCCC(=O)N1CCOCC1

Procedure:
Example 1(A) was repeated using morpholine, potassium carbonate and dodecanoyl chloride in a biphasic mixture of chloroform and water followed by the usual workup to obtain the above product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C@H:7]([OH:9])[CH3:8])=[CH:3][CH:2]=1.C(O)(=O)C>CO.O=[Pt]=O>[NH:1]1[CH2:6][CH2:5][CH:4]([C@H:7]([OH:9])[CH3:8])[CH2:3][CH2:2]1
Reactant: C[C@@H](O)c1ccncc1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H](O)C1CCNCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.8 %

Procedure:
A solution of (1R)-1-(4-pyridinyl)ethanol (37 g, 0.3 mol, 78% ee) in MeOH (2 L) was charged with PtO2 (5 g) under nitrogen atmosphere followed by acetic acid (19 mL). The mixture was evacuated and purged with hydrogen several times and then stirred under an atmosphere of hydrogen for 2 d at room temperature. The mixture was filtered to remove catalyst and the filtrate was concentrated in vacuo and triturated with EtOAc to yield a cream-colored solid which was collected by filtration. The filter cake was dissolved in MeOH (500 mL) and 50% NaOH (15.8 g) was added. The resulting solution was stirred at 25° C. for 30 min and concentrated. The resulting solid was triturated with Et2O (700 mL) and stirred at 25° C. for 30 min, the solids were removed by filtration and the filtrate was dried over MgSO4 and filtered again. The final filtrate was concentrated to yield (1R)-1-(4-piperidinyl)ethanol (22 g, 57% yield) as a light beige solid. 1H NMR (400 MHz, CDCl3): δ 3.50 (quint, 1H, J=6.3 Hz), 3.13-3.01 (m, 2H), 2.61-2.47 (m, 2H), 1.88 (br, 2H), 1.84-1.73 (m, 1H), 1.63-1.52 (m, 1H), 1.41-1.27 (m, 1H), 1.23-1.05 (m, 2H), 1.13 (d, 3H, J=6.2 Hz).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C@H:2]1[CH2:3][OH:4].[CH2:8]([CH:10]1O[CH2:11]1)[Cl:9]>>[Cl:9][CH2:8][C@@H:10]1[O:4][CH2:3][C@@H:2]2[CH2:5][CH2:6][CH2:7][N:1]2[CH2:11]1
Reactant: OC[C@@H]1CCCN1
Reactant: ClCC1CO1
Product: ClC[C@H]1CN2CCC[C@H]2CO1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 14.8 %

Procedure:
(S)-(+)-Prolinol (6.00 g, 59.3 mmol) was added to epichlorohydrin (47 mL, 600 mmol) at 0° C. The solution was stirred at 40° C. for 0.5 h and then concentrated in vacuo. The residual oil was cooled in an ice bath and concentrated sulfuric acid (18 mL) was added dropwise with stirring. The mixture was heated at 170-180° C. for 1.5 h, poured into ice (300 mL) and then basified with sodium carbonate to pH˜8. The mixture was partitioned with ethyl acetate/hexanes and filtered. The filtrate was separated and the aqueous portion was extracted twice with ethyl acetate. The combined organic portion was dried over sodium sulfate, filtered and concentrated in vacuo to afford oil that was purified by column chromatography (ethyl acetate for less polar product and then 30% methanol in ethyl acetate). (3S,8aS)-3-(Chloromethyl)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine (less polar product) (1.87 g, 10.7 mmol, 18% yield): 1H NMR (400 MHz, CDCl3): 4.06 (dd, 1H), 3.79-3.71 (m, 1H), 3.60-3.48 (m, 2H), 3.36 (dd, 1H), 3.15 (dd, 1H), 3.13-3.06 (m, 1H), 2.21-2.01 (m, 3H), 1.90-1.68 (m, 3H), 1.39-1.24 (m, 1H); MS (EI) for C8H14NOCl: 176 (MH+). (3R,8aS)-3-(Chloromethyl)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine (1.54 g, 8.77 mmol, 15% yield): 1H NMR (400 MHz, CDCl3): 3.94-3.77 (m, 4H), 3.55 (dd, 1H), 3.02-2.93 (m, 2H), 2.45 (dd, 1H), 2.29-2.15 (m, 2H), 1.88-1.64 (m, 3H), 1.49-1.38 (m, 1H); MS (EI) for C8H14NOCl: 176 (MH+).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][C:13]3[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:20](/B(O)O)=[CH:21]\[CH2:22][CH2:23][CH2:24][CH3:25]>>[CH:20](/[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][C:13]3[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)=[CH:21]\[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: Cc1cnc(CNc2ccc3ncc(Br)n3n2)cn1
Reactant: CCCC/C=C/B(O)O
Product: CCCC/C=C/c1cnc2ccc(NCc3cnc(C)cn3)nn12
Yield: 40 %

Procedure:
Prepared from the product of step A and (E)-1-hexeneboronic acid according to general procedure 2 providing the title compound (20 mg, 40%) as a brown solid; 1H NMR (500 MHz, CD3OD) δ 8.55 (s, 1H), 8.48 (s, 1H), 7.60 (d, J=9.5 Hz, 1H), 7.39 (s, 1H), 6.75 (d, J=9.5 Hz, 1H), 6.51-6.40 (m, 2H), 4.67 (s, 2H), 2.52 (s, 3H), 2.20-2.15 (m, 2H), 1.42-1.34 (m, 4H), 0.94 (t, J=7.0 Hz, 3H); 13C NMR (125 MHz, CD3OD) δ 154.8, 153.4, 153.1, 144.9, 143.4, 137.9, 133.2, 129.3, 128.6, 126.0, 116.6, 113.1, 45.9, 34.4, 32.8, 23.4, 20.9, 14.3; HPLC tR=14.6 min (Luna), 98.1%; ES-MS: (M+H)=323 m/z.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][S:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][N:26]1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][N:26]4[C:30](=[O:31])[C:29]5=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]5[C:27]4=[O:36])[CH2:13][CH2:14]3)=[N:7][S:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)nsc2c1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCN1CCC(c2nsc3cc(F)ccc23)CC1

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (4.72 g, 0.02 mole), potassium carbonate (4.14 g, 0.03 mole) and N-(2-bromoethyl)phthalimide (6.35 g, 0.0025 mole) in 200 ml of acetonitrile is heated at reflux for 4 hours. The solids are then removed by filtration and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography over silica gel to provide N-[2-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]ethyl]phthalimide.
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[C:12]1([CH3:30])[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:28][CH:27]([OH:29])[CH2:26][C@H:22]2[C:23](O)=[O:24])(=[O:20])=[O:19])=[CH:14][CH:13]=1>O1CCCC1>[OH:24][CH2:23][C@@H:22]1[CH2:26][C@@H:27]([OH:29])[CH2:28][N:21]1[S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:30])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: Cc1ccc(S(=O)(=O)N2CC(O)C[C@H]2C(=O)O)cc1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)N2C[C@H](O)C[C@H]2CO)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To 2 l of tetrahydrofuran (THF) was added 57.6 g (1523 mmol) of sodium borohydride and the mixture was cooled to 10° C. before 250 ml (1980 mmol) of borontrifluoride etherate was added dropwise over a period of 1 hour. Then 215.3 g (755.4 mmol) of 1-(4-toluenesulfonyl)-4-hydroxy-L-proline was added carefully in 100 ml of THF and the mixture was allowed to stir for 16 hours. The reaction was quenched with methanol and 10% aqueous hydrogen chloride solution was added and the mixture was gently heated to 60° C. for 1 hour. The reaction mixture was filtered and the pH was adjusted to neutral with 50% aqueous sodium hydroxide solution and the volatiles were evaporated under reduced pressure. The product was then isolated via filtration and the filter cake was washed with water. Drying under vacuum at 60° C. for 12 hours yielded 164 g of the product as a white solid in 85 % yield. M.P. 132°-133° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.CN(C)C=O.C(Cl)(=O)C([Cl:19])=O>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([Cl:19])=[O:10])[CH2:4][CH2:3]1
Reactant: CN1CCC(C(=O)O)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCC(C(=O)Cl)CC1
Temperature: 20 °C

Procedure:
A flask was flame dried and placed under a nitrogen atmosphere. 1-methylpiperidine-4-carboxylic acid (1 eq) in anhydrous methylene chloride added to flask and cooled to 20° C. in a water bath. Dimethylformamide added, then oxalyl chloride (1.4 eq) in methylene chloride. Reaction refluxed for 2 hours, brought to room temperature, concentrated and azeotroped with toluene to yield 1-methylpiperidine-4-carbonyl chloride as a light yellow fluffy solid. MS: MH+=162.
Reaction SMILES: Cl.O1CCOC[CH2:3]1.[Cl:8][C:9]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]>CO>[CH3:3][O:12][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:9]=1[Cl:8]
Reactant: Cc1ccc(C(=O)O)c(Cl)c1
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc(C)cc1Cl
Temperature: 25 °C
Yield: 87 %

Procedure:
Add 4N hydrogen chloride in 1,4-dioxane (20 mL, 80 mmol) to 2-chloro-4-methylbenzoic acid (5.0 g, 29.3 mmol) in methanol (60 mL). Stir the reaction mixture at room temperature over the weekend. Concentrate the reaction mixture and partition the residue between ethyl acetate and saturated aqueous sodium bicarbonate solution. Separate the organic layer and extract the aqueous with ethyl acetate (2×). Combine the organic layers, wash with brine, dry over sodium sulfate, and concentrate to provide the title compound as a brownish oil (4.7 g, 25.5 mmol).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:6]([C:7]2[CH:8]=[C:9]([CH2:22]O)[CH:10]=[CH:11][C:12]=2[C:13]2[C:18]([F:19])=[CH:17][N:16]=[C:15]([O:20][CH3:21])[CH:14]=2)=[CH:5][CH2:4][CH2:3]1.CN(C=O)C.S(Cl)([Cl:32])=O>C(Cl)Cl>[Cl:32][CH2:22][C:9]1[CH:10]=[CH:11][C:12]([C:13]2[C:18]([F:19])=[CH:17][N:16]=[C:15]([O:20][CH3:21])[CH:14]=2)=[C:7]([C:6]2[C:2]([CH3:24])([CH3:1])[CH2:3][CH2:4][CH:5]=2)[CH:8]=1
Reactant: COc1cc(-c2ccc(CO)cc2C2=CCCC2(C)C)c(F)cn1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(-c2ccc(CCl)cc2C2=CCCC2(C)C)c(F)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (3-(5,5-dimethylcyclopent-1-enyl)-4-(5-fluoro-2-methoxypyridin-4-yl)phenyl)methanol T8.3 (34.5 mg, 105 μmol) was added DCM (1.1 mL) and DMF (8.2 μL, 105 μmol) followed by thionyl chloride (15 μL, 211 μmol) in an ice bath. The reaction was then stirred at room temperature for 1 hour. The reaction was concentrated and directly purified on silica gel to afford 4-(4-(chloromethyl)-2-(5,5-dimethylcyclopent-1-enyl)phenyl)-5-fluoro-2-methoxypyridine T8 (36 mg) as an oil (99%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:30])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([C:20]34[CH2:29][CH:24]5[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]5)[CH2:21]3)[CH2:27]4)[CH:13]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+].O>CO>[OH:3][CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:30])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([C:20]34[CH2:29][CH:24]5[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]5)[CH2:21]3)[CH2:27]4)[CH:13]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: COc1ccc(C(=O)Nc2ccc(C(C)=O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc(C(C)O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 48 h
Yield: 66 %

Procedure:
The amide obtained in Example 23, above, (0.9 g, 2 mmoles) is dissolved in methanol (25 ml) and treated with 0.12 g (3 mmoles) of sodium borohydride. The mixture is stirred at ambient temperature for 2 days, poured into water and extracted with ether. The extracts are dried on magnesium sulfate, then the solvent is evaporated. The resulting residue is recrystallized in ethyl acetate to give N[4-[1-hydroxyethyl)phenyl]-3-(1-adamantyl)-4-methoxy benzamide (0.5 g, 66% yield) having a melting point of 207°-209° C.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:25])(=[O:5])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].Cl.[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37]Cl.O>CN(C)C=O>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[O:25][CH2:37][CH2:36][CH2:35][N:34]([CH3:39])[CH3:33])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccc(F)cc1C
Reactant: CN(C)CCCCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(=O)c1cnc2c(OCCCN(C)C)cccc2c1Nc1ccc(F)cc1C
Reaction time: 1 h
Yield: 10.9 %

Procedure:
3-Butyryl-4-(4-fluoro-2-methylphenylamino)-8-hydroxyquinoline (3.38 g, 10 mmol) and potassium t-butoxide (3.05 g, 25 mmol) were dissolved in dimethyl formamide (30 ml), warmed to 70° and 3-dimethylaminopropyl chloride hydrochloride (1.90 g, 12 mmol) added. The mixture was stirred for 1 hour at 80° then a further portion of potassium t-butoxide (2.44 g, 20 mmol) and 3-dimethylaminopropyl chloride hydrochloride (1.58 g, 10 mmol) added, and stirring continued overnight. A third portion of potassium t-butoxide (2.44 g, 20 mmol) and 3-dimethylaminopropyl chloride hydrochloride (1.58 g, 10 mmol) was added and the temperature raised to 85° . After a further 5 hours the mixture was poured into water, extracted with ether and the ether extracts dried and evaporated. Chromatography (silica gel, 4-6% methanolic ammmonia in dichloromethane) and recrystallisation from ethyl acetate gave 3-butyryl-4-(4-fluoro-2-methylphenyl-amino)-8-(3-dimethylaminopropoxy)quinoline (0.46 g, 11%), m.p. 99°-100°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[CH:10][N:11]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=1.C([N-]C(C)C)(C)C.[Li+].[Si:40]([O:47][C:48]1[C:49]([F:58])=[C:50]([CH:53]=[C:54]([CH2:56][CH3:57])[CH:55]=1)[CH:51]=[O:52])([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH:51]([C:50]2[CH:53]=[C:54]([CH2:56][CH3:57])[CH:55]=[C:48]([O:47][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[C:49]=2[F:58])[OH:52])[N:11]([C:13]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:12]=1
Reactant: Brc1ccccc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCc1cc(C=O)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cc(O[Si](C)(C)C(C)(C)C)c(F)c(C(O)c2nc(-c3ccccc3Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
To a solution of Intermediate 217.1 (650 mg, 1.40 mmol) in 10 mL THF at 0° C., was added a solution of lithium diisopropylamide (2M in heptane/THF/ethylbenzene, 0838 mL, 1.68 mmol). The mixture was stirred at 0° C. for 30 min, then a solution of Intermediate 188.3 (356 mg, 1.26 mmol) in 2 mL THF. The mixture was stirred at 0° C. for 2 h, then was quenched with sat. NH4Cl and diluted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 40% EtOAc/hexanes gradient) to afford 510 mg of Intermediate 217.2 as a pale yellow solid. LCMS (50 to 100% B, 4 min gradient, A=95% H2O/5% CH3CN/0.1% TFA, B=5% H2O/95% CH3CN/0.1% TFA) RT=5.61 min, 747.67 (M+H)+.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C@H:19]3[CH2:24][CH2:23][C@H:22]([CH2:25][O:26]CC4C=CC(OC)=CC=4)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[N:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(#N)C.[N+]([O-])([O-])=O.[NH4+]>O>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C@H:19]3[CH2:20][CH2:21][C@H:22]([CH2:25][OH:26])[CH2:23][CH2:24]3)=[CH:15][CH:14]=2)=[N:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(-c2ccc([C@H]3CC[C@H](COCc4ccc(OC)cc4)CC3)cc2)nc1
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CCCCCCc1ccc(-c2ccc([C@H]3CC[C@H](CO)CC3)cc2)nc1

Procedure:
A mixture of 0.485 g of 5-hexyl-2-[p-(trans-4-(p-anisyloxymethyl)cyclohexyl)phenyl]pyridine, 9.6 ml of acetonitrile and 2.4 ml of water is treated at 0° C. with 1.25 g of cer-(IV) ammonium nitrate. After 10 minutes the reaction mixture is diluted with water and extracted with diethyl ether. The organic phase is washed several times with water, then dried over magnesium sulphate and evaporated. Purification of the residue by chromatography on silica gel gives 5-hexyl-2-[p-(trans-4-(hydroxymethyl)-cyclohexyl)phenyl]pyridine.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([C:22]3[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=3[F:29])[C:4]=2[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[N:7]=1.[CH3:30][C:31]1[C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([OH:35])=[O:34].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:13]([N:12]([CH2:15][CH3:16])[CH2:11][CH2:10][CH2:9][NH:8][C:6]1[N:7]=[C:2]([C:39]2[C:31]([CH3:30])=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33]([OH:35])=[O:34])[C:3]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([C:22]3[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=3[F:29])[C:4]=2[N:5]=1)[CH3:14]
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1C(=O)O
Reactant: CCN(CC)CCCNc1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 150 °C
Yield: 109.2 %

Procedure:
To the compound 4-chloro-2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)pyrido[2,3-d]pyrimidin-7(8H)-one (176 mg, 0.418 mmol) in dioxane (4.5 mL) and water (1.5 mL) was added 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (173 mg, 0.626 mol), potassium carbonate (289 mg, 2.09 mmol) and tetrakis(triphenylphosphine)palladium(0) (24.2 mg, 0.0259 mmol). The mixture was heated with microwave at about 150° C. for about 15 min. The mixture was filtered. Separation by HPLC with TFA afforded the title compound (238 mg, 99%). LC-MS m/z 522 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:19])[CH2:14][S:15][CH:16]([CH3:18])[CH3:17])[CH2:9]1)=O)(C)(C)C.[H-].[Na+].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25](F)[C:24]=1[C:30]([F:33])([F:32])[F:31].CCO>CN(C=O)C.Cl>[Cl:22][C:23]1[C:24]([C:30]([F:31])([F:32])[F:33])=[C:25]([CH:26]=[CH:27][CH:28]=1)[O:19][C@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:14][S:15][CH:16]([CH3:17])[CH3:18]
Reactant: Fc1cccc(Cl)c1C(F)(F)F
Reactant: CC(C)SC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)SC[C@H](Oc1cccc(Cl)c1C(F)(F)F)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-3-((R)-1-Hydroxy-2-isopropylsulfanylethyl)pyrrolidine-1-carboxylic acid t-butyl ester (10 mg, 0.030 μmol) was dissolved in DMF (166 μL). NaH (1.7 mg, 69.1 μmol) was added and the mixture was stirred at room temperature for 15 minutes. 2-Chloro-6-fluorobenzotrifluoride (20.6 mg, 104 μmol) was added and the mixture was stirred at 100° C. for 1 hour. The mixture was cooled to room temperature, concentrated then dissolved in 1.2M HCl in EtOH (1.0 mL, 1.2 mmol) and stirred overnight at room temperature. The product was concentrated and the crude product was dissolved in 1:1 AcOH/H2O (1.5 mL) then purified by preparative HPLC to yield the title compound as a mono-TFA salt (9.2 mg, purity 94%). MS m/z: [M+H]+ calcd for C16H21ClF3NOS, 368.10; found 368.0.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16](OS(C)(=O)=O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN1C(=O)N(C)CCC1.CCOCC>[CH:1]([N:14]1[CH2:17][CH:16]([NH:30][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CN1CCCN(C)C1=O
Solvent: CCOCC
Product: c1ccc(CNC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 70 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
To a solution of methanesulfonic acid 1-benzhydrylazetidin-3-yl ester (0.32 g, 1 mmol) in N,N′-dimethylpropyleneurea (0.5 ml) was added benzylamine (0.5 ml, 5 mmol), and the mixture was stirred at 70° C. for 18 h. It was then cooled to room temperature and diluted with ether (30 ml). The resulting suspension was filtered and the ether solution was evaporated. The residue was partitioned between hexanes and water, and hexanes solution was washed with saturated sodium bicarbonate solution and dried over anhydrous sodium sulfate. It was then filtered through a pad of silica gel, and the filter pad was eluted with a 1:1 mixture of ether-hexanes. Evaporation of solvents followed by trituration with isooctane gave 0.22 g of a white solid; m.p. 73-75° C.; MS (ES) m/z 329.0 (MH+); HRMS (EI) Calcd. for C23H24N2 (M+): 328.1940, Found: 328.1936.
Reaction SMILES: C(O[C:4]([C:6]1[C:10]([Cl:11])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:8][N:7]=1)=[O:5])C.C(O[C:20]([C:22]1[N:23](CCNC(OC(C)(C)C)=O)N=C(COC2C=CC=CC=2)C=1)=O)C.C(OC(C1C=C2C(=O)NCCN2N=1)=O)C>>[CH2:15]([O:14][C:12]([C:9]1[C:10]([Cl:11])=[C:6]2[C:4](=[O:5])[NH:23][CH2:22][CH2:20][N:7]2[N:8]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)c1n[nH]c(C(=O)OCC)c1Cl
Reactant: CCOC(=O)c1cc(COc2ccccc2)nn1CCNC(=O)OC(C)(C)C
Agent: CCOC(=O)c1cc2n(n1)CCNC2=O
Product: CCOC(=O)c1nn2c(c1Cl)C(=O)NCC2

Procedure:
The compound was prepared from 4-chloro-1H-pyrazole-3,5-dicarboxylic acid diethyl ester and 2-(2-tert-butoxycarbonylamino)ethyl bromide using the methods described in the preceding examples 5 (2-(2-tert-butoxycarbonylamino-ethyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester) and 48 (4,5,6,7-tetrahydro-4-oxo-pyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester.