Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]([C:11]1([CH3:15])[CH2:14][O:13][CH2:12]1)[C:5]1[O:6][C:7]([CH3:10])=[CH:8][CH:9]=1)=[N+]=[N-].[H][H]>C(O)C.[Pd]>[CH3:10][C:7]1[O:6][C:5]([CH:4]([NH2:1])[C:11]2([CH3:15])[CH2:12][O:13][CH2:14]2)=[CH:9][CH:8]=1
Reactant: [H][H]
Reactant: Cc1ccc(C(N=[N+]=[N-])C2(C)COC2)o1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(C(N)C2(C)COC2)o1
Yield: 97.9 %

Procedure:
A solution of 1.68 g (8 mmol, 1 eq) of 2-[azido-(3-methyloxetan-3-yl)methyl]-5-methylfuran in 30 ml of ethanol in the presence of 252 mg (15% by weight) of palladium on carbon at 10% was stirred at hydrogen atmospheric pressure for 3 hours. The reaction medium was filtered and the filtrate was evaporated. 1.42 g of C-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine were obtained in the form of a greenish oil. Yield=98%.
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=[CH:10][C:9]([OH:19])=[CH:8][CH:7]=2)([CH3:3])[CH3:2].[CH2:20]([O:22][C:23](=[O:28])[C:24](Br)([CH3:26])[CH3:25])[CH3:21]>>[CH2:20]([O:22][C:23](=[O:28])[C:24]([O:19][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[C:12]2[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)([CH3:26])[CH3:25])[CH3:21]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CC(C)c1[nH]c2ccc(O)cc2c1-c1ccncc1
Product: CCOC(=O)C(C)(C)Oc1ccc2[nH]c(C(C)C)c(-c3ccncc3)c2c1

Procedure:
The above compound was prepared from 2-isopropyl-3-(4-pyridyl)-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[O-]CC.[Na+].[Na].[CH:14]([C:16]([CH3:18])=[O:17])=[CH2:15]>C(O)C.C(Cl)(Cl)Cl>[O:17]=[C:16]([CH3:18])[CH2:14][CH2:15][P:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4]
Reactant: CCOP([O-])OCC
Reactant: C=CC(C)=O
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOP(=O)(CCC(C)=O)OCC
Temperature: 15 °C

Procedure:
To 243 grams (1.76 moles) of diethyl phosphite stirred under nitrogen and protected by a drying tube was added a solution of sodium ethoxide prepared from 5.07 grams (0.22 mole) of sodium in 100 ml of anhydrous ethanol. Methyl vinyl ketone, 112 grams (1.60 moles), was then added at such a rate as to keep the temperature at 35°-40° C. The addition required about one hour. The reaction mixture was stirred for one-half hour after the addition was completed and was stripped to dryness in vacuo at 60° C./16 mm. The residue was taken up in 600 ml of chloroform, and the solution cooled to 15° C. and washed successively with dilute acid, water and saturated sodium chloride solution. After drying, the chloroform solution was distilled to yield 112 grams of diethyl 3-oxobutylphosphonate as a colorless liquid, B.P. 106° C./0.05 mm, nD 25 1.4340. VPC indicated that the product was 90% pure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][C:11]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([O:25]C)=[O:24])(=[O:16])=[O:15])=[O:12])[N:4]=1.[OH-].[K+].Cl>C(O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][C:11]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([OH:25])=[O:24])(=[O:16])=[O:15])=[O:12])[N:4]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(OC)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)O)n1
Reaction time: 24 h

Procedure:
4.0 g of N-[(4-methoxy-6-methylpyrimidin-2-yl)aminocarbonyl]-2-methoxycarbonylbenzenesulfonamide was dissolved in a mixture of 20 ml of absolute ethanol, 2.5 ml of water and 2.5 g of potassium hydroxide. After stirring at 25° for 24 hours the mixture had become a semi-solid mass. Enough cold water was added to dissolve the solid and the solution was acidified to pH 3 with concentrated hydrochloric acid. The resultant precipitate was isolated by filtration and washed with cold water. The precipitate was dried to afford 3.7 g of the title compound, melting at 195°-200°. The nuclear magnetic resonance spectrum exhibited resonances for the methyl and methoxy substituents on the pyrimidine ring at 2.67 ppm and 4.20 ppm respectively.
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[C:5]([CH3:10])[N:4]=1.ClCCl>CO.[O-2].[O-2].[Mn+4]>[OH:9][C:8]1[C:3]([C:2]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:1])=[N:4][C:5]([CH3:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(O)c(C(O)c2ccccc2)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(O)c(C(=O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
2-(Hydroxy-phenyl-methyl)-6-methyl-pyridin-3-ol (553 mg) was dissolved in methanol (3 ml) and dichloromethane (9 ml) to prepare a solution. Manganese dioxide (2.05 g) was added to the solution, and the mixture was stirred at room temperature overnight. The reaction solution was filtered through Celite and was then washed with chloroform and methanol. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give (3-hydroxy-6-methyl-pyridin-2-yl)-phenyl-methanone (439 mg, yield 80%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:31])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][NH2:30])=[CH:25][CH:24]=2)[N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:39]1([C:42](Cl)=[O:43])[CH2:41][CH2:40]1>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:31])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][NH:30][C:42]([CH:39]3[CH2:41][CH2:40]3)=[O:43])=[CH:25][CH:24]=2)[N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CC1
Reactant: NCc1ccc(-c2csc(NC(=O)C3CCCN3C(=O)OCc3ccccc3)n2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1ccc(-c2csc(NC(=O)C3CCCN3C(=O)OCc3ccccc3)n2)cc1)C1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-[4-(4-Aminomethyl-phenyl)-thiazol-2-ylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (Compound 5379, Example 379, 100 mg, 0.23 mmol) was dissolved in 5 mL of dry CH2Cl2. To this solution at 0° C. was added triethylamine (0.035 mL, 0.46 mmol) followed by cyclopropanecarbonyl chloride (48 mg, 0.46 mmol). The reaction mixture was stirred at 0° C. for 30 minutes and then quenched using H2O. The organic phase was isolated and evaporated under reduced pressure to yield the crude product, which was then purified using reverse phase HPLC. MS: 505.2(M+H−); H1 NMR (DMSO-d6): δ(ppm) 12.41 (s, 1H), 8.58 (s, 1H), 7.82 (d, 2H), 7.57 (d, 1H), 7.31 (dd, 4H), 7.10 (dd, 3H), 5.00 (m, 2H), 4.45 (m, 1H), 4.23 (d, 2H), 3.48 (m, 2H), 2.21 (m, 1H), 1.89 (m, 3H), 1.60 (m, 1H), 0.60 (d, 4H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:23]([F:26])([F:25])[F:24])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])[C:7]([CH:20]1[CH2:22][CH2:21]1)=[CH:6]2)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:3]1[C:4]([C:23]([F:26])([F:25])[F:24])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([OH:15])=[O:14])[C:7]([CH:20]1[CH2:22][CH2:21]1)=[CH:6]2)#[N:2]
Reactant: CC(C)(C)OC(=O)Cn1c(C2CC2)cc2c(C(F)(F)F)c(C#N)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc2c(cc(C3CC3)n2CC(=O)O)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
To a suspension of 1,1-dimethylethyl [5-cyano-2-cyclopropyl-4-(trifluoromethyl)-1H-indol-1-yl]acetate (Example 362A) (1.23 g, 4 mmol) in dry CH2Cl2 (10 mL) was added TFA (3.1 mL, 40 mmol) at rt. The mixture was stirred at rt overnight. Solvent and excess TFA were removed in vacuo. The residue was titrated with Et2O-hexanes to afford the title compound (1.05 g, 85%): MS (ES) m/z 309 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@H:12]([C:14]2[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])[O:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+].Cl[Si](C)(C)C.CO>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][O:11][C@@H:12]([C:14]2[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Br)cc1[C@H]1CN(Cc2ccccc2)C(=O)CO1
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Br)cc1[C@H]1CN(Cc2ccccc2)CCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
A solution of (6S)-4-benzyl-6-(5-bromo-2-methoxyphenyl)-morpholin-3-one (67.2 g, 179 mmol) in tetrahydrofuran (200 ml) was added to an ice-cooled mixture of lithium borohydride (8.55 g, 393 mmol) and chlorotrimethylsilane (99.7 ml, 785 mmol) in tetrahydrofuran (500 ml) over 45 minutes and the solution was stirred at same temperature for one hour and then at room temperature for 5 hours. After careful addition of methanol (60 ml) to the ice-cooled solution, solvent was removed under reduced pressure and the residue in 10% aqueous sodium hydroxide (280 ml) was stirred at 90° C. for 3 hours. The solvents were removed under reduced pressure and the residue was partitioned between water and diethyl ether. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by silica gel column chromatography (hexane/ethyl acetate) gave (2S)-4-benzyl-2-(5-bromo-2-methoxyphenyl)-morpholine (46.1 g, 71%, 2 steps) as a yellow oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([C:19](=[O:34])[CH2:20][C:21]2[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=2)[O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:16]=[CH:17][CH:18]=1.[BH4-].[Na+]>CCO.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]([OH:34])[CH2:20][C:21]2[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=2)[O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)COc1cccc(CC(=O)c2cccc(OCc3ccc4ccccc4n3)c2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)COc1cccc(CC(O)c2cccc(OCc3ccc4ccccc4n3)c2)c1
Reaction time: 0.5 h

Procedure:
The product obtained from Step B (5 mmol) in 50 mL of EtOH is treated with (2 mmol) of NaBH4 at room temperature. After 30 min, the reaction mixture is diluted with water and extracted with EtOAc. The organic solution is dried and evaporated and purified by dry column chromatography to give ethyl 2-(3-(2-(3-(2-quinolinylmethyloxy)phenyl)-2-hydroxyethyl)phenoxy)acetate.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:29])[CH2:23][NH:24][C:25](=[O:28])[CH2:26][OH:27])[CH3:21])[C:14]=3[Cl:30])[C:5]2=[N:4][C:3]=1[CH3:31].C(N(CC)CC)C.[S:39](Cl)([CH3:42])(=[O:41])=[O:40]>C(Cl)Cl>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:29])[CH2:23][NH:24][C:25](=[O:28])[CH2:26][O:27][S:39]([CH3:42])(=[O:41])=[O:40])[CH3:21])[C:14]=3[Cl:30])[C:5]2=[N:4][C:3]=1[CH3:31]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CO)c3Cl)cccn2c1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)COS(C)(=O)=O)c3Cl)cccn2c1Br
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a solution of 3-bromo-8-[2,6-dichloro-3-[N-(glycoloylglycyl)-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (200 mg) and triethylamine (76 mg) in methylene chloride (2 ml) was dropwise added mesyl chloride (52 mg) under ice-cooling, and the mixture was stirred for 1 hour at the same temperature. The mixture was washed with water twice and brine, dried over magnesium sulfate and concentrated in vacuo to give 3-bromo-8-[2,6-dichloro-3-[N-(mesyloxyacetylglycyl)-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (221 mg).
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][C:6]1[CH:23]=[C:22]2[O:24][CH2:25][O:26][C:21]2=[CH:20][C:7]=1[CH2:8][N:9]1C(=O)C2=CC=CC=C2C1=O)[CH3:2].NN.C(O)C>ClCCl>[CH2:1]([O:3][CH2:4][O:5][C:6]1[CH:23]=[C:22]2[O:24][CH2:25][O:26][C:21]2=[CH:20][C:7]=1[CH2:8][NH2:9])[CH3:2]
Reactant: CCOCOc1cc2c(cc1CN1C(=O)c3ccccc3C1=O)OCO2
Agent: NN
Solvent: ClCCl
Solvent: CCO
Product: CCOCOc1cc2c(cc1CN)OCO2

Procedure:
N-(2-Ethoxymethoxy-4,5-methylenedioxybenzyl)phthalimide (1.70 g, 4.77 mmol) was treated with 0.5 mL (16 mmol) hydrazine in 90 mL refluxing ethanol for three hr. The reaction mixture was cooled and the phthalhydrazide was removed by filtration and washed three times with ethyl ether. The organic solutions were combined and evaporated to dryness on a rotary evaporator to yield a residue, which was taken up in dichloromethane. The organic solution was washed three times with 10% sodium hydroxide and the combined aqueous solutions were back-extracted with dichloromethane two times. The combined organic solutions were washed with brine and dried over sodium sulfate/potassium carbonate. Evaporation of the solvent gave of 2-ethoxymethoxy-4,5-methylenedioxybenzylamine as a slightly yellow liquid (0.98 g, 92% yield) that solidified upon standing. IR: 3298 cm-1. 1HNMR (200 MHz): δ 6.77 (1H, s); 6.75 (1H, s); 5.91 (2H, s); 5.18 (2H, s); 3.74 (2H, q, J=7.1 Hz); 3.73 (2H, s); 1.45 (2H, br s); and 1.24 ppm 3H, t,J=7.1 Hz).
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-])=O)[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.[H][H]>[Pd].C(O)C.O>[F:1][C:2]1[CH:30]=[C:29]([NH2:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCCCN1CCOCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: COc1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Yield: 49.8 %

Procedure:
A reactor containing 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-(3-morpholin-4-yl propoxy)quinoline (2.5 kg) and 10 percent palladium on carbon (50 percent water wet, 250 g) in a mixture of ethanol and water containing concentrated hydrochloric acid (1.5 L) was pressurized with hydrogen gas (approximately 40 psi). The mixture was stirred at ambient temperature. When the reaction was complete (typically 2 hours), as evidenced by in process HPLC analysis, the hydrogen was vented and the reactor inerted with argon. The reaction mixture was filtered through a bed of Celite® to remove the catalyst. Potassium carbonate was added to the filtrate until the pH of the solution was approximately 10. The resulting suspension was stirred at 20 to 25° C. for approximately 1 hour. The solids were collected by filtration, washed with water, and dried at 50 to 60° C. under reduced pressure to afford the title compound (1.164 kg). 1H NMR (400 MHz, DMSO-d6): δ 8.45 (d, 1H), 7.51 (s, 1H), 7.38 (s, 1H), 7.08 (t, 1H), 6.55 (dd, 1H), 6.46 (dd, 1H), 6.39 (dd, 1H), 5.51 (br. s, 2H), 4.19 (t, 2H), 3.94 (s, 3H), 3.59 (t, 4H), 2.47 (t, 2H), 2.39 (m, 4H), 1.98 (m, 2H). LC/MS Calcd for [M+H]+ 428.2. found 428.1.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][C@H:9]3[NH:20][CH2:19][CH2:18][C@@:15]4([C:16]=2[CH:17]=1)[C@H:10]3[CH2:11][CH2:12][C:13](=[O:21])[CH2:14]4.[CH:22]1([CH2:25]Br)[CH2:24][CH2:23]1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CO>[ClH:1].[CH:22]1([CH2:25][N:20]2[CH2:19][CH2:18][C@@:15]34[C:16]5[CH:17]=[C:4]([O:3][CH3:2])[CH:5]=[CH:6][C:7]=5[CH2:8][C@@H:9]2[C@@H:10]3[CH2:11][CH2:12][C:13](=[O:21])[CH2:14]4)[CH2:24][CH2:23]1
Reactant: BrCC1CC1
Reactant: COc1ccc2c(c1)[C@]13CCN[C@H](C2)[C@@H]1CCC(=O)C3
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)[C@]13CCN(CC4CC4)[C@H](C2)[C@@H]1CCC(=O)C3

Procedure:
A sample of 3-methoxymorphinan-6-one hydrochloride (3.08 g, 10 mmol, prepared in Part IC), was reacted with cyclopropylmethyl bromide in the presence of sodium bicarbonate as described in Example 1D. After chromatography on Silica Gel G using 20:1 V/V chloroform-methanol, 2.5 g of the desired product was isolated as a syrup. This was converted to the hydrochoride salt to yield 2.1 g (58%) of TR-5152, mp 265°-267° C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[C:15](=O)([O:24][C@H:25]1[CH2:29][CH2:28][O:27][CH2:26]1)[O:16]N1C(=O)CCC1=O.CCN(C(C)C)C(C)C>C1COCC1>[CH3:12][C:11]([CH3:14])([CH3:13])[C@H:3]([NH:2][C:15]([O:24][C@H:25]1[CH2:29][CH2:28][O:27][CH2:26]1)=[O:16])[C:4]([O:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:5]
Reactant: O=C(O[C@H]1CCOC1)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)[C@@H](N)C(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)[C@@H](NC(=O)O[C@H]1CCOC1)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 55.1 %

Procedure:
A mixture of (S)-tert-butyl 2-amino-3,3-dimethylbutanoate hydrochloride (0.05 g, 0.223 mmol), (S)-2,5-dioxopyrrolidin-1-yl tetrahydrofuran-3-yl carbonate (0.056 g, 0.246 mmol) and Hunig's base (0.078 mL, 0.447 mmol) in THF (2.25 mL) was stirred at room temperature for 12 hours. The solvent was evaporated and the product was purified by chromatography on silica gel eluting with 0-15% ethyl acetate in dichloromethane to give the title compound (0.037 g, 55% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C@@H:11]([CH2:23][CH2:24][C:25]([NH:27][NH2:28])=[O:26])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:29](Cl)(Cl)Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:14])=[O:15])[C@@H:11]([CH2:23][CH2:24][C:25]3[O:26][CH:29]=[N:28][N:27]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: ClC(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)N2[C@@H](CCC(=O)NN)CC[C@H]2c2ccc(F)cc2)cc1
Product: Cc1ccc(S(=O)(=O)N2[C@@H](CCc3nnco3)CC[C@H]2c2ccc(F)cc2)cc1

Procedure:
The title compound, light yellow oil, MS: m/e=416.1 (M+H+) and [α]D20=−80.1° (c=0.2211 in chloroform), was prepared in accordance with the general method of example 127 from (2R,5S)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionic acid hydrazide and triethyl orthoformiate.
Reaction SMILES: [NH2:1][C:2]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5].[Cl:15]N1C(C)(C)C(=O)N(Cl)C1=O>C(O)(=O)C>[NH2:1][C:2]1[C:13]([F:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:3]=1[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5]
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Reactant: CON(C)C(=O)c1cccc(F)c1N
Solvent: CC(=O)O
Product: CON(C)C(=O)c1cc(Cl)cc(F)c1N
Yield: 86.6 %

Procedure:
To a solution of 2-amino-3-fluoro-N-methoxy-N-methyl-benzamide (765 mg, 3.86 mmol) in acetic acid (18 ml) was added 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (783 mg, 2.7 mmol) at room temperature. The orange solution was stirred over night and was then poured carefully onto ice/saturated NaHCO3-solution. The mixture was extracted with EtOAc and the combined extracts were washed with brine, dried with Na2SO4 and evaporated. The remaining residue was purified by column chromatography (silica gel, heptane/EtOAc 90:10-80:20) to afford the title compound (544 mg, 61%) as light brown solid. MS (ESI): 233.0 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:7][C:8]([CH3:29])=[C:9]([C:25]([O:27][CH3:28])=[O:26])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[Cl:24])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].S(O)(O)(=O)=O.CS[C:37](=[NH:39])[NH2:38].C(N(CC)CC)C>C(O)CC>[Cl:24][C:18]1[C:19]([Cl:23])=[CH:20][CH:21]=[CH:22][C:17]=1[CH:10]1[C:9]([C:25]([O:27][CH3:28])=[O:26])=[C:8]([CH3:29])[NH:7][C:6]([CH2:5][O:4][CH2:3][CH2:2][NH:1][C:37]([NH2:39])=[NH:38])=[C:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CCCO
Product: CCOC(=O)C1=C(COCCNC(=N)N)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Yield: 74.9 %

Procedure:
2-(2-Aminoethoxymethyl)-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (5.0 g) and S-methylisothiourea sulphate (3.45 g) was suspended in n-propanol (120 ml) and triethylamine (30 ml) and refluxed for 17 hours. After evaporation to dryness, the residual oil was partitioned between aqueous sodium bicarbonate and methylene chloride. The organic layer was dried (MgSO4), filtered and evaporated. The resultant beige solid was triturated with hexane to give the title compound (4.1 g), N.M.R. (CDCl3, 60 MHz): 3H 1.15(t), 3H 3.55(s), 4H 3.7(m), 2H 4.0(q), 2H 4.7(s), 1H 5.45(s), 8H 7.25(m).
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1>CO>[C:1]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)#[N:2]
Reactant: Oc1ccc(CCl)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CO
Product: N#CCc1ccc(O)cc1
Yield: 45 %

Procedure:
A solution of p-chloromethyl phenol in acetonitrile (Example 12) was reacted with equimolar sodium cyanide in excess methanol (800 parts methanol/mole sodium cyanide) and the reaction mixture was refluxed for one hour. The oil after solvent evaporation (washed as in Experiment 18) was fractionated to yield 45% of α-cyano-p-cresol (b.p. 150°-155°/1 mm. of mercury; M.P. 68°-70°). Infrared spectra confirmed the identity of the product.
Reaction SMILES: [C:1]1([C:11]([N:13]2[CH2:17][C@@H:16]([CH:18]3[CH2:20][CH2:19]3)[C@H:15]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6]C=CC=2)[CH:4]=[CH:3][CH:2]=1.C(C1C=CC=C2C=1[N:45]([CH2:47][CH2:48][CH2:49][NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH:44]=C2)(O)=O>>[C:54]([O:53][C:51]([NH:50][CH2:49][CH2:48][CH2:47][N:45]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][C:1]=2[C:11]([N:13]2[CH2:17][C@@H:16]([CH:18]3[CH2:20][CH2:19]3)[C@H:15]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[CH2:14]2)=[O:12])[CH:6]=[CH:44]1)=[O:52])([CH3:57])([CH3:56])[CH3:55]
Reactant: CC(C)(C)OC(=O)NCCCn1ccc2cccc(C(=O)O)c21
Reactant: O=C(c1cccc2ccccc12)N1C[C@@H](CN2CCC(c3ccc(F)cc3)CC2)[C@H](C2CC2)C1
Product: CC(C)(C)OC(=O)NCCCn1ccc2cccc(C(=O)N3C[C@@H](CN4CCC(c5ccc(F)cc5)CC4)[C@H](C4CC4)C3)c21
Yield: 5.4 %

Procedure:
1-(N-(3-t-butoxycarbonylaminopropyl)-7-indolecarbonyl)-3-(R)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(S)-(cyclopropyl)pyrrolidine (0.13 g) was prepared from 0.125 g (4 mmol) of 3-(S)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(S)-(cyclopropyl)pyrrolidine (Example 9) and 0.13 g (4.3 mmol) of 7-carboxy-N-(3-t-butoxycabonylaminopropyl)indole as described in Example 11. It was purified by chromatography (silica, acetone:hexanes, 3:7).
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[CH3:30][N:31]([CH3:36])[CH2:32][CH2:33][CH2:34][NH2:35]>>[F:23][C:22]1[CH:21]=[C:20]([CH3:24])[CH:19]=[C:18]([F:25])[C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:35][CH2:34][CH2:33][CH2:32][N:31]([CH3:36])[CH3:30])=[O:29])[S:14][N:13]=1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1
Reactant: CN(C)CCCN
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCN(C)C)c2C(N)=O)c(F)c1

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and N,N-dimethyl-propane-1,3-diamine by the procedure analogous to Example 1. MS (APCI, m/z): 428 [M+H]+.