Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10]2[C:15]3[C:16]4[CH:22]=[C:21]([C:23]([CH3:25])=[CH2:24])[CH:20]=[N:19][C:17]=4[NH:18][C:14]=3[CH:13]=[N:12][C:11]=2[C:26]#[N:27])[CH2:5][CH2:4]1)[CH3:2]>[Pd].C(N(CC)CC)C>[CH2:1]([N:3]1[CH2:4][CH2:5][CH:6]([O:9][C:10]2[C:15]3[C:16]4[CH:22]=[C:21]([CH:23]([CH3:24])[CH3:25])[CH:20]=[N:19][C:17]=4[NH:18][C:14]=3[CH:13]=[N:12][C:11]=2[C:26]#[N:27])[CH2:7][CH2:8]1)[CH3:2]
Reactant: C=C(C)c1cnc2[nH]c3cnc(C#N)c(OC4CCN(CC)CC4)c3c2c1
Agent: [Pd]
Solvent: CCN(CC)CC
Product: CCN1CCC(Oc2c(C#N)ncc3[nH]c4ncc(C(C)C)cc4c23)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.4 %

Procedure:
A suspension of 5-(1-ethylpiperidin-4-yloxy)-3-isopropenyl-9H-dipyrido[2,3-b:4′,3′-d]pyrrole-6-carbonitrile (98 mg, 0.271 mmol), 10% palladium on carbon (50 mg) and triethylamine (0.5 mL) in IMS (5 mL) was stirred at ambient temperature under a hydrogen atmosphere for 18 h. The mixture was filtered through a PTFE filter and the filtrate concentrated in vacuo to give a brown solid. The resultant solid was purified by flash chromatography (silica, 12 g column, ISCO, 0-5% MeOH in DCM) to afford the title compound as a white solid (27 mg, 27%). 1H NMR (DMSO-D6, 300 MHz): 12.96 (s, 1H), 8.82 (s, 1H), 8.68 (s, 1H), 8.32 (s, 1H), 5.11-4.77 (m, 1H), 3.65-3.48 (m, 2H), 3.28-3.18 (m, 2H), 3.14-2.90 (m, 3H), 2.42-2.18 (m, 4H), 1.37 (d, J=6.9 Hz, 6H), 1.29-1.17 (m, 3H). LCMS (Method H): RT=7.10 min, M+H+=364.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:12])[CH3:11])=[CH:2]1.[N:13]([CH2:16][CH2:17][CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([CH3:28])=[CH:25][CH:26]=2)[C:21](=[O:29])[C:20]1=[O:30])=[N+:14]=[N-:15].CNC>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:12])[CH2:11][C:21]2([OH:29])[C:22]3[C:27](=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=3)[N:19]([CH2:18][CH2:17][CH2:16][N:13]=[N+:14]=[N-:15])[C:20]2=[O:30])=[CH:2]1
Reactant: CC(=O)c1c[nH]c2ccccc12
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2CCCN=[N+]=[N-]
Agent: CNC
Solvent: CO
Product: Cc1ccc2c(c1)C(O)(CC(=O)c1c[nH]c3ccccc13)C(=O)N2CCCN=[N+]=[N-]
Temperature: 130 °C

Procedure:
To a clean Biotage microwave vial was added 1-(1H-indol-3-yl)ethanone (0.023 grams, 0.143 mmol, purchased from Fisher Scientific), 1-(3-azidopropyl)-5-methylindoline-2,3-dione (0.02 grams, 0.082 mmol) and 0.27 mL of methanol. After the addition of 9.0 μL of dimethyl amine (40% by weight solution in water, purchased from Fisher Scientific), the vial was sealed and heated in a Biotage Initiator for ten minutes at 130° C. It was then concentrated and purified using a Teledyne ISCO hexanes/ethyl acetate gradient on silica gel. A subsequent purification was done using a preparative thin layer chromatography (ethyl acetate, hexanes (2:1)). Yield 14%. 1H-NMR δ 8.87 (bs, 1H), 8.34 (m, 1H), 7.76 (s, 1H), 7.40 (m, 1H), 7.29 (m, 3H), 7.10 (d, 1H), 6.77 (d, 1H), 5.0 (bs, OH), 3.77 (m, 2H), 3.60 (d, 1H), 3.41 (t, 2H), 3.34 (d, 1H), 2.27 (s, 3H), 1.96 (m, 2H).
Reaction SMILES: [CH:1]1([C:7]([C:9]2[N:10]([CH3:14])[CH:11]=[CH:12][CH:13]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:15][S:16](O)(=[O:18])=[O:17]>>[CH:1]1([C:7]([C:9]2[N:10]([CH3:14])[C:11]([S:16]([Cl:15])(=[O:18])=[O:17])=[CH:12][CH:13]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=S(=O)(O)Cl
Reactant: Cn1cccc1C(=O)C1CCCCC1
Product: Cn1c(C(=O)C2CCCCC2)ccc1S(=O)(=O)Cl
Temperature: 60 °C
Yield: 79.6 %

Procedure:
To a solution of compound 25b (1.0 g, 5.2 mmol) was added portionwise chlorosulfonic acid (5 mL, 75 mmol) at 0° C., heated to 60° C. for 2 h, poured carefully into ice-water and extracted with CHCl3. The organic phase was dried (MgSO4), evaporated and purified by CC to give compound 25c (1.2 g, 80%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[C:15]([F:18])([F:17])[F:16])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([O-])=O.[H][H]>[Pt]=O.C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[C:15]([F:16])([F:17])[F:18])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1ccc(C(F)(F)F)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CCOC(=O)c1ccc(C(F)(F)F)c(N)c1
Yield: 77 %

Procedure:
A mixture of 395 mg (1.50 mmol) of ethyl 3-nitro-4-(trifluoromethyl)benzoate (from Step C), 20 mg of platinum oxide, and 6 mL of ethanol was shaken with hydrogen at 3-4 atm. for a few hours, by which time the reaction was essentially complete. The catalyst was removed by filtration, and the filtrate was concentrated to dryness. The residue was chromatographed on silica gel (elution with 25:1 hexane-EtOAc) to afford a 77% yield of the title compound as a pale yellow, gummy foam; TLC in 4:1 hexane-EtOAc; mass spectrum (EI) m/e 233 (M+). 200 MHz 1H NMR (CD3OD) δ1.36 (t, J=7.1 Hz, 3H), 4.33 (q, J=7.1 Hz, 2H), 7.26 (d, J=8 Hz, 1H), 7.44 (d, J=8 Hz, 1H) overlapping 7.47 (s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=O.[NH2:17][C:18]([NH2:20])=[S:19]>C(O)C>[NH2:20][C:18]1[S:19][CH:2]=[C:3]([CH:5]2[CH2:9][CH2:8][CH2:7][N:6]2[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)CCl
Reactant: NC(N)=S
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC1c1csc(N)n1

Procedure:
An ethanol (20 mL) solution of tert-butyl 2-(2-chloroacetyl)pyrrolidine-1-carboxylate (1.08 g, 4.4 mol) and thiourea (334 mg, 4.4 mmol) was stirred at 55 C for 70 hours. Upon completion of the condensation, the solution was evaporated. The solid was dissolved in CH2Cl2 (100 mL). It was washed with dilute NaHCO3 solution, dried and evaporated. Recrystallization from CH2Cl2/hexane afforded tert-butyl 2-(2-aminothiazol-4-yl)pyrrolidine-1-carboxylate. 1H NMR (400 MHz, CDCl3): mixture of rotamers: δ 8.81 (s, 2H, br), 6.22 and 6.15 (2s, 1H), 4.84 and 4.78 (2s, 1H), 3.62 and 3.44 (2m, 2H), 2.4-1.8 (m, 4H), 1.46 and 1.36 (2s, 9H). MS (ES+): M/Z 270 (M+H)+, 170 (M−C5H8O2)+.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[CH:2]=[C:3]=[CH2:4].[Cl:9][C:10]1[CH:11]=[C:12]([C:17](=[N:19][OH:20])C)[CH:13]=[CH:14][C:15]=1[Cl:16]>C(Cl)Cl>[CH2:7]([O:6][C:1](=[O:5])[CH2:2][C:3]1[O:20][N:19]=[C:17]([C:12]2[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([Cl:9])[CH:11]=2)[CH:4]=1)[CH3:8]
Reactant: CC(=NO)c1ccc(Cl)c(Cl)c1
Reactant: C=C=CC(=O)OCC
Solvent: ClCCl
Product: CCOC(=O)Cc1cc(-c2ccc(Cl)c(Cl)c2)no1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a solution of ethyl 2,3-butadienoate (1 eq) and 1-(3,4-dichloro-phenyl)-ethanone oxime (1.03 eq) in DCM (51 vol) was added a 10% aqueous bleach solution (51 vol) and the resultant biphasic system stirred at room temperature for 5 days. The organic layer was separated and the aqueous layer extracted with DCM (3×7 vol). The combined organic layers were washed with water (36 vol), dried over MgSO4, filtered and concentrated. The crude residue was purified by a combination of flash column chromatography (eluent: [0:1 to 1:2] EtOAc:heptane) and prep HPLC to yield [3-(3,4-Dichloro-phenyl)-isoxazol-5-yl]-acetic acid ethyl ester.
Reaction SMILES: [CH3:1][N:2]1[CH:11]=[C:10]2[C:4]([C:5](=[O:14])[CH2:6][CH2:7][NH:8][S:9]2(=[O:13])=[O:12])=[CH:3]1.Cl[CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:31][C:28]1[CH:27]=[CH:26][C:25]([N:22]2[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][CH2:16][N:8]3[CH2:7][CH2:6][C:5](=[O:14])[C:4]4=[CH:3][N:2]([CH3:1])[CH:11]=[C:10]4[S:9]3(=[O:13])=[O:12])[CH2:24][CH2:23]2)=[CH:30][CH:29]=1
Reactant: Cn1cc2c(c1)S(=O)(=O)NCCC2=O
Reactant: Fc1ccc(N2CCN(CCCCl)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cn1cc2c(c1)S(=O)(=O)N(CCCN1CCN(c3ccc(F)cc3)CC1)CCC2=O
Yield: 57.7 %

Procedure:
A suspension of 236 mg (1.1 mmol) of Compound 15, 308 mg (1.2 mmol) of 1-(3-chloropropyl)-4-(4-fluorophenyl)piperazine and 304 mg (2.2 mmol) of potassium carbonate in 15 ml of 2-butanone was refluxed for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: ethyl acetate), whereby 276 mg of the title compound were obtained (yield: 58%).
Reaction SMILES: [CH:1]1([C:4]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=O)[CH2:3]C1.[BH4-].[Na+].C(O)(=[O:18])C>C(O)C>[CH:4]1([CH:6]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[OH:18])[CH2:1][CH2:3]1
Reactant: CC(=O)O
Reactant: O=C(Cc1ccc(F)cc1)C1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC(c1ccc(F)cc1)C1CC1
Reaction time: 6 h

Procedure:
Add 3.2 g (0.085 mole) cyclopropyl-4-fluorobenzylmethanone to 80 ml of 3.2 g (0.085 mole) sodium borohydride partially dissolved in absolute ethanol, following the reaction by thin-layer chromatography. After about 6 hours at room temperature, cool the reaction in an ice bath and add acetic acid. Extract the mixture with methylene (3×60 ml) wash the methylene chloride extracts with saturated aqueous sodium bicarbonate solution, and dry over magnesium sulfate. Evaporate the methylene chloride extracts and dry in vacuo to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)=[CH:10][C:11](=[O:18])[NH:12][C:13]=2[C:14]([F:17])([F:16])[F:15])=[CH:4][CH:3]=1.Br[CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:30]([O:18][C:11]1[CH:10]=[C:9]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][CH:20]=2)[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:13]([C:14]([F:15])([F:17])[F:16])[N:12]=1)[CH3:31]
Reactant: CCBr
Reactant: CS(=O)(=O)c1ccc(-c2cc(=O)[nH]c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)c(C(F)(F)F)n1
Reaction time: 20 h
Yield: 26.4 %

Procedure:
A mixture of 0.11 g of 5-(4-fluorophenyl)-4-[4(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-oxo-pyridine (step 5 of Example 1), 3,3 g of bromoethane, 0.2 g of potassium carbonate, and 5 mL of dimethyl formamide (DMF) was stirred for 20 hours and concentrated in vacuo. The residue was triturated with water and extracted with methylene chloride. The methylene chloride extract was dried over MgSO4 and filtered through silica gel. The filtrate was reconcentrated in vacuo and the residue was crystallized from methylene chloride/hexane to give 31 mg of solid: mp 168.5°-170.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1)=[CH:5]2.[Li]CCCC.CON(C)[C:32](=[O:36])[CH2:33][CH2:34][CH3:35]>C1COCC1>[C:32]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1)=[CH:5]2)(=[O:36])[CH2:33][CH2:34][CH3:35]
Reactant: CCCC(=O)N(C)OC
Reactant: Cn1c(C2CCN(C(=O)OC(C)(C)C)C2)cc2cc(Br)ccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC(=O)c1ccc2c(c1)cc(C1CCN(C(=O)OC(C)(C)C)C1)n2C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 69.9 %

Procedure:
To solution of tert-butyl 3-(5-bromo-1-methyl-1H-indol-2-yl)pyrrolidine-1-carboxylate (1.207 g, 3.18 mmol) in THF (13 mL) at −78° C. was added solution of n-BuLi (2.5M hexanes, 1.50 mL, 3.75 mmol) dropwise over 10 min. The reaction was stirred at −78° C. for 10 min, then a solution of N-methoxy-N-methylbutyramide (0.50 g, 3.81 mmol) in THF (2.0 mL) was added dropwise. The reaction was slowly allowed to warm to −50° C. before it was quenched with NH4Cl (aqueous saturated, 10 mL). Once ambient temperature was reached in the reaction mixture, the product was extracted with EtOAc (3×20 mL). Combined organics were washed with NaCl (aqueous saturated) and dried over Na2SO4. Upon solvent removal residue was purified by column chromatography using EtOAc/hexanes (gradient 0-60%) to afford tert-butyl 3-(5-butyryl-1-methyl-1H-indol-2-yl)pyrrolidine-1-carboxylate (0.823 g) in 70% yield.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([OH:15])=[C:10]([CH3:16])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C1COCC1>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([CH3:16])[C:11]([O:15][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:12]([CH3:14])[N:13]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: Cc1nc(-n2c(C)ccc2C)nc(C)c1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-n2c(C)ccc2C)nc(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution containing 1.62 g (7.46 mmol) of 2-(2,5-dimethyl-1H-pyrrol-1-yl)-5-hydroxy-4,6-dimethylpyrimidine (5) in 30 mL of anhydrous THF were added 440 mg (11.00 mmol) of 60% sodium hydride suspension in mineral oil followed by 1.20 mL (10.10 mmol) of benzyl bromide. The reaction mixture was stirred at room temperature under argon atmosphere for 48 h. The reaction mixture was poured into 150 mL of water and extracted with two portions of 100 mL of ethyl acetate. The combined organic solution was washed with a portion of 100 of brine, dried (MgSO4) and then concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column. Elution with hexanes-ethyl acetate 4:1 gave the expected product as light yellow oil: yield 2.20 g (96%). 1H-NMR (CDCl3) δ 7.42 (m, 5H), 5.86 (s, 2H), 4.92 (s, 2H), 2.47 (s, 6H), 2.29 (s, 6H); 13C-NMR (CDCl3) δ 161.59, 152.34, 147.66, 136.05, 129.16, 128.59, 128.26, 107.90, 75.29, 19.10, 14.10.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[F:10])#[N:2].C([O-])([O-])=O.[Na+].[Na+].[NH2:17][OH:18].Cl>CCO.O>[NH2:7][C:6]1[CH:8]=[CH:9][C:3]([C:1](=[N:17][OH:18])[NH2:2])=[C:4]([F:10])[CH:5]=1
Reactant: N#Cc1ccc(N)cc1F
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=NO)c1ccc(N)cc1F
Temperature: 60 °C

Procedure:
4-cyano-3-fluoroaniline (10 g, 0.073 mol) dissolved in EtOH (36 ml). Water (7.3 ml) was added followed by Na2CO3 (5.06 g, 0.65 eq) and the temperature of the mixture raised to 60° C. NH2OH.HCl (5.6 g, 1.1 eq) in water (7.3 ml) was added slowly, and the mixture heated at 60° C. overnight. The mixture was cooled to rt, the solid was collected by filtration, washed with, water (7 ml), EtOH (7 ml), ether (20 ml), and dried to give 7.5 g of M16-1.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][OH:31])[CH:25]=1>>[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][O:31][C:3]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=3[Cl:16])[C:6]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[CH:5][N:4]=2)[CH:25]=1
Reactant: CSc1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: OCc1cccnc1
Product: Clc1ccc(-c2cnc(OCc3cccnc3)nc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
2-Methylthio-5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)pyrimidine from Reference Example 3 was reacted with 3-pyridinemethanol according to the procedure described in Example 59 to afford 2-(3-pyridylmethoxy)-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine (HRf): HPLC/MS: m/e=442 (M++1); Rt=3.01 min; 1H-NMR 500 MHz (CDCl3): δ 5.61 (s, 2H), 7.05 (d, J=9 Hz, 2H), 7.15-7.22 (m, 1H), 7.24-7.32 (m, 4H), 7.50-7.58 (m, 1H), 7.60 (m, 1H), 7.62-7.63 (m, 1H), 8.45 (m, 1H), 8.83 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH2:14]/[CH:15]=[CH:16]/[CH:17]=O)[CH2:7][CH2:6]2.[CH2:19]([NH:26][C:27]([CH3:33])=[CH:28][C:29]([O:31][CH3:32])=[O:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([N:26]1[CH:17]=[CH:16][CH:15]([CH2:14][CH:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]2=[O:13])[C:28]([C:29]([O:31][CH3:32])=[O:30])=[C:27]1[CH3:33])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)C=C(C)NCc1ccccc1
Reactant: COc1ccc2c(c1)CCC(C/C=C/C=O)C2=O
Product: COC(=O)C1=C(C)N(Cc2ccccc2)C=CC1CC1CCc2cc(OC)ccc2C1=O

Procedure:
The title compound 69 is prepared according to the procedure reported in step D of Example 8 with aldehyde 54 (100 mg, 0.41 mmol) and enamine 70 (90.0 mg, 0.37 mmol) as reactants. Purification by column chromatography on SiO2 (Petroleum Ether/EtOAc=2:1) afford the title compound 69 as a yellow oil. (Yield 80 mg, 45%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH3:9])[N:3]=1.BrC1C=CC(S(C)=[O:18])=NC=1>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH3:9])=[O:18])[N:3]=1
Reactant: CS(=O)c1ccc(Br)cn1
Reactant: CSc1cccc(Br)n1
Product: CS(=O)c1cccc(Br)n1

Procedure:
The title compound was prepared from 2-bromo-6-methylsulfanyl-pyridine following a procedure analogous to that described for 5-bromo-2-methanesulfinyl-pyridine in Example 182. Mass spectrum (ESI+): m/z=220/222 (Br) [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]=[S:12])([CH3:3])[CH3:2].[CH2:13]([NH:15][CH2:16][C:17](O)=[O:18])[CH3:14].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:13]([N:15]1[CH2:16][C:17](=[O:18])[N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]([CH3:3])[CH3:2])[C:11]1=[S:12])[CH3:14]
Reactant: CC(C)c1ccccc1N=C=S
Reactant: CCNCC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(c2ccccc2C(C)C)C1=S
Yield: 42.9 %

Procedure:
The title compound was prepared by the procedure described in Example 16 using 15.42 g of 2-isopropylphenyl-isothiocyanate, 16.05 g of N-ethyl glycine, 12 g of triethyl amine, and 200 mL of chloroform. Purification was achieved by flash chromatography on silica gel (5-20 % ethyl acetate in hexane) Crystallization from ethanol afforded the title compound (9.8 g) as a white solid, m.p. 125°-127° C. Anal. Calcd. for. C14H18N2O S: C, 64.09; H, 6.91; N, 10.68. Found: C, 64.19 H, 6.93; N, 10.71. Mass spectrum (EI, M.+) m/z 262.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:12]([OH:14])=O)[CH3:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:15]1([C@@H:21]([CH2:23][OH:24])[NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:12]([NH:22][C@@H:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:23][OH:24])=[O:14])[CH3:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N[C@H](CO)c1ccccc1
Reactant: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Product: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)N[C@H](CO)c1ccccc1

Procedure:
Following General Procedure E and using N-(3,4-dichlorophenyl)-D,L-alanine (from Example A above) and (S)-(+)-2-phenylglycinol (Aldrich), the title compound was prepared as a solid (mp=66-70° C.). The reaction was monitored by tlc on silica gel (Rf=0.25 in 5% methanol/methylene chloride) and purification was by flash column chromatography (silica gel using 5% methanol/methylene chloride as eluent).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[Br:19][C:20]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:21]=1N.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[Br:19][C:20]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:21]=1[NH:13][C:12]1[C:11]2[C:10](=[CH:9][CH:8]=[C:6]3[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]3=2)[N:14]=[CH:15][N:16]=1
Reactant: Nc1ccc(F)cc1Br
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(F)cc4Br)c3c2s1
Yield: 44 %

Procedure:
Prepared from VII and 2-bromo-4-fluoroaniline. Flash chromatography eluent (DCM-EtOAc, 95:5). Yield: 44%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 3068, 2853, 2228, 1736, 1644, 1611, 1582, 1497, 1474, 1459, 1380, 1353, 1309, 1252, 1188, 1171, 1127, 1050, 1031, 980, 881, 860, 826; 19F NMR (282 MHz, DMSO-d6) δ −119.33; 1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, 1H, J=9.0 Hz), 8.18 (s, 1H), 7.81 (d, 1H, J=9.0 Hz), 7.63 (d, 1H, J=7.8 Hz) 7.24-7.17 (m, 2H); HRMS calcd for C16H8N5SBrF (M+H+): 399.9668, found 399.9675.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([CH:11]1[CH2:15][S:14][CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH2:23][CH2:24][O:25][N+:26]([O-:28])=[O:27])[NH:12]1)([OH:10])=[O:9].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[C:1]([N:12]1[CH:11]([C:8]([OH:10])=[O:9])[CH2:15][S:14][CH:13]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH2:23][CH2:24][O:25][N+:26]([O-:28])=[O:27])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)C1CSC(c2ccccc2OCCO[N+](=O)[O-])N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N1C(C(=O)O)CSC1c1ccccc1OCCO[N+](=O)[O-]
Reaction time: 1 h
Yield: 60 %

Procedure:
A solution of 0.9 ml of acetic anhydride in THF was added slowly at 0° C. to a solution of 2 g of the compound from Example XVI and 2.1 g of potassium carbonate in H2O. The resulting solution was stirred for 1 hour, after which 1.0 g of potassium carbonate was added to the reaction mixture, followed by the addition of 1 ml of acetic anhydride. The reaction mixture was stirred for one and a half hours, after which a further 1.0 g of potassium carbonate and 1 ml of acetic anhydride were added. After finally stirring for a further 30 minutes, the solution was concentrated under vacuum and cooled in ice. The addition of dilute sulphuric acid gave a precipitate. This precipitate was filtered off, dried and recrystallised from methanol/ether. Yield 60%. Empirical formula C14H16N2O7S. Molecular weight 356. Melting point 159°-162° C. TLC system: ethyl acetate:methanol/1:1. Rf 0.50.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Br:35][C:36]1[CH:37]=[C:38]([C:43]([F:46])([F:45])[F:44])[C:39](O)=[N:40][CH:41]=1.C(P(CCCC)CCCC)CCC.C(OC(C)C)(C)C>C1(C)C=CC=CC=1>[Br:35][C:36]1[CH:37]=[C:38]([C:43]([F:46])([F:44])[F:45])[C:39]([O:1][CH2:2][CH2:3][CH:4]2[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]2)=[N:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: Oc1ncc(Br)cc1C(F)(F)F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CC(C)OC(C)C
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ncc(Br)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
tert-Butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (7.7 g) and 1,1′-(azodicarbonyl)dipiperidine (11.6 g) were added to a mixture of 5-bromo-3-(trifluoromethyl)pyridine-2-ol (7 g) and toluene (124 mL) at room temperature. Tributylphosphine (11.6 mL) was added thereto under ice-cooling, and the mixture was stirred at room temperature overnight. After diisopropylether was added to the reaction mixture, the mixture was stirred, and the insoluble material was separated by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Hex:EtOAc=100:0 to 70:30), whereby tert-butyl 4-(2-{[5-bromo-3-(trifluoromethyl)pyridin-2-yl]oxy}ethyl)piperidine-1-carboxylate (8.93 g) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:6])[CH:4]=[CH2:5].[CH2:7]([NH2:9])[CH3:8]>>[CH2:7]([NH:9][CH2:5][CH2:4][C:3]([NH:2][CH3:1])=[O:6])[CH3:8]
Reactant: C=CC(=O)NC
Reactant: CCN
Product: CCNCCC(=O)NC
Yield: 98.7 %

Procedure:
N-methylacrylamide (ABCR: 851 mg, 10.00 mmol) and ethylamine (2 M in methanol, 10 mL, 20.00 mmol) were combined in a microwave reaction vessel, which was sealed and irradiated at 140° C. for 30 mins. The reaction mixture was allowed to cool and then loaded directly onto a 50 g SCX-2 cartridge, washing with methanol (100 mL) and eluting the desired product with 7 N methanolic ammonia (100 mL). Concentration under reduced pressure of product containing fractions gave the title compound as a clear oil (1.285 g; 99%)