Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][C:15](=[O:17])[CH2:16][CH:9]1[CH2:10][O:11][CH2:12]2)=O)(C)(C)C.[BH4-].[Na+].FC(F)(F)C(O)=O>CO.C(Cl)Cl>[CH:9]12[NH:8][CH:13]([CH2:14][CH:15]([OH:17])[CH2:16]1)[CH2:12][O:11][CH2:10]2
Reactant: CC(C)(C)OC(=O)N1C2COCC1CC(=O)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC1CC2COCC(C1)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 7-oxo-3-oxa-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester (100 mg, 0.41 mmol) in MeOH (5 mL) was added NaBH4 (47 mg, 1.24 mmol) in one portion at room temperature. The mixture was stirred at room temperature overnight, and then quenched with sat. NaHCO3. The mixture was extracted with EtOAc (20 mL) three times. The organic layer was washed with sat. NaHCO3 and brine (20 mL) respectively. The organic layer was dried over Na2SO4, and then filtered. The solvent was concentrated under reduced pressure to give a crude product La, which was dissolved in CH2Cl2 (5 mL). Trifluoroacetic acid (2 mL) was added to the solution dropwise at 0° C. After being stirred at room temperature for 2 hours, the mixture was concentrated under reduced pressure. The residue was further dried on high-vacuum to give 3-oxa-9-aza-bicyclo[3.3.1]nonan-7-ol (Compound L) which was directly used for next step. MS: calc'd (MH+) 144, measured (MH+) 144.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl.[CH2:33]([N:40]1[CH2:45][CH2:44][CH2:43][CH2:42][C@@H:41]1[CH2:46]Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:46][CH:41]3[CH2:42][CH2:43][CH2:44][CH2:45][N:40]3[CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:27])([F:28])[F:29])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrC[C@H]1CCCCN1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)c[nH]2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CC2CCCCN2Cc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
To a solution of 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (4.5 g, 0.011 mol, 1.0 eq) in DMSO (100 mL) and add powdered KOH (3.0 g, 0.055 mol, 5.0 eq) at RT under nitrogen atmosphere and stir for 30 minutes. To the resulting solution add (R)-1-benzyl-2-(bromomethyl)piperidine hydrochloride (5.0 g, 0.0165 mol, 1.5 eq) and stir the reaction mass at RT for 16 h. After completion, dilute the reaction with water (100 mL) and extract the compound in EA (3×100 mL). Wash the organic layer with brine (2×50 mL) and dry over anhydrous sodium sulfate. Concentrate the organic layer under reduced pressure and purify on silica (100-200 mesh) using 2% acetone-DCM to get 3.0 g (46%) of the title compound. (ES+): m/z=601 (M+H).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]3[O:15]C[O:13][C:10]=3[CH:11]=2)[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[N:4]1)[CH3:2].B(Br)(Br)Br.[CH3:24]O>ClCCl>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([OH:15])=[C:10]([OH:13])[CH:11]=2)[C:6](=[O:16])[C:5]([C:17]([O:19][CH3:24])=[O:18])=[N:4]1)[CH3:2]
Reactant: CCn1nc(C(=O)O)c(=O)c2cc3c(cc21)OCO3
Reactant: CO
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCn1nc(C(=O)OC)c(=O)c2cc(O)c(O)cc21
Temperature: -30 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a suspension of 1-ethyl-4-oxo-1,4-dihydro-[1,3]dioxolo[4,5-g]cinnoline-3-carboxylic acid (12.6 g, 48.1 mmol) in dichloromethane (DCM) (50 mL) stirred under nitrogen at −30° C. was added dropwise a solution of boron tribromide (168 mL, 168 mmol) in dichloromethane (140 mL). The white suspension turned yellowish. The mixture was kept at −30° C. for 1 h and then allowed to warm up to room temperature, and stirred for 40 h. The reaction mixture was again cooled to −30° C., methanol (100 mL) was added, and the resulting mixture was stirred at room temperature over the weekend. The organic solvents were partially removed to afford a light yellow suspension. The solid was collected by filtration and washed with dichloromethane (20 mL). The filtrate was concentrated again to provide more yellow solids that was collected and washed by dichloromethane (20 mL). The solids were combined to afford methyl 1-ethyl-6,7-dihydroxy-4-oxo-1,4-dihydrocinnoline-3-carboxylate (11 g, 35.8 mmol, 74.5% yield). LCMS: (M+H)+: 265.0
Reaction SMILES: CS([C:5]1[N:15]=[C:8]2[N:9]=[C:10]([CH3:14])[CH:11]=[C:12]([CH3:13])[N:7]2[N:6]=1)(=O)=O.[CH:16]1([CH2:21][CH2:22][CH2:23][OH:24])[CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([CH2:21][CH2:22][CH2:23][O:24][C:5]2[N:15]=[C:8]3[N:9]=[C:10]([CH3:14])[CH:11]=[C:12]([CH3:13])[N:7]3[N:6]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1cc(C)n2nc(S(C)(=O)=O)nc2n1
Reactant: OCCCC1CCCC1
Product: Cc1cc(C)n2nc(OCCCC3CCCC3)nc2n1
Yield: 52 %

Procedure:
The title compound was prepared according to the experimentals described for Example 11 above from 2-methanesulfonyl-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine and 3-cyclopentyl-1-propanol in 52% yield. EM (calc.): 274.2; MS (ESI) m/e: 275.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:26])/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(O)(=O)C.C(O)(=O)C(O)=O.[CH:37]1([CH2:42][NH2:43])[CH2:41][CH2:40][CH2:39][CH2:38]1.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:26])/[CH:16]=[CH:17]/[C:18]3[CH:19]=[CH:20][C:21]([CH2:24][NH:43][CH2:42][CH:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)=[CH:22][CH:23]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: NCC1CCCC1
Reactant: O=C(/C=C/c1ccc(CCl)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccc(CNCC2CCCC2)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
A reaction mixture of 200 mg (0.523 mmol) of (E)-N-(4′-chlorobiphenyl-4-yl)-3-(4-chloromethylphenyl)acrylamide, 295 mg (1.56 mmol) of cyclopentylmethylamine oxalic acid acetate and 0.44 mL (3.12 mmol) of triethylamine in 5 mL of THF is refluxed for 18 hours. Then the reaction mixture is poured onto water and the precipitate formed is suction filtered. Further purification is carried out by column chromatography on silica gel (eluant: dichloromethane/methanol (10:1)). Yield: 10 mg (4% of theory); C28H29ClN2O (M=445.0); melting point: 209° C.-210° C.; calc.: molecular ion peak (M+H)+: 445/447 (Cl); found: molecular ion peak (M+H)+: 445/447 (Cl).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH2:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:14]=1>CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH:12][S:19]([C:15]3[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=3)(=[O:21])=[O:20])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Nc1cc(F)cc2cccnc12
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1cc(F)cc2cccnc12)c1cccnc1
Yield: 31.9 %

Procedure:
In a similar fashion using route 14 general procedure 27, 6-fluoroquinolin-8-amine (Intermediate 48) (100 mg, 0.62 mmol), pyridine 3-sulfonyl chloride (Intermediate 17) (130 mg, 0.74 mmol) and DMAP (cat.) gave the title compound (60 mg, 32%) after purification by column chromatography with n-hexane/DCM (1:0-0:1) gradient elution followed by recrystallisation from DCM/n-pentane.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:20]=[CH:19][C:7]2[S:8][C:9]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:10]=3[CH2:11][C:12](=[O:13])[C:6]=2[CH:5]=1)[CH3:2].O>CO.C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:20]=[CH:19][C:7]2[S:8][C:9]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:10]=3[CH2:11][CH:12]([OH:13])[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc2c(c1)C(=O)Cc1c(Cl)cccc1S2
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: CCOc1ccc2c(c1)C(O)Cc1c(Cl)cccc1S2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
An amount of 31.8 g of 2-ethoxy-9-chloro-10,11 -dihydrodibenzo[b,f]thiepin-11-one was dissolved in 200 ml of a mixed solvent of methanol and chloroform (5/1) and the mixture was stirred at room temperature for 2 hours and freed of the solvent to obtain the residue. To the resulting residue was added 100 ml of water and the mixture was extracted with chloroform. The extract was washed with water, dried over anhydrous sodium sulfate and freed of the solvent to obtain the residue.
Reaction SMILES: Cl.NC1C2C(=CC(CC(NC(=O)CNS(C3C(C)=C(C)C4OC(C)(C)CCC=4C=3C)(=O)=O)C(=O)N3CCCCC3)=CC=2)C=CN=1.[NH2:46][C:47]1[C:56]2[C:51](=[CH:52][C:53]([CH2:57][CH:58]([NH:67][C:68](=[O:74])OC(C)(C)C)[C:59](=[O:66])[N:60]3[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]3)=[CH:54][CH:55]=2)[CH:50]=[CH:49][N:48]=1.[CH3:75][O:76][C:77]1[CH:82]=[C:81]([CH3:83])[C:80]([S:84]([NH:87][C@@H:88]([CH2:92][CH:93]([CH3:95])[CH3:94])C(O)=O)(=[O:86])=[O:85])=[C:79]([CH3:96])[C:78]=1[CH3:97].N[C@H](C(O)=O)CC(C)C.COC1C=C(C)C(S([Cl:119])(=O)=O)=C(C)C=1C>>[ClH:119].[NH2:46][C:47]1[C:56]2[C:51](=[CH:52][C:53]([CH2:57][CH:58]([NH:67][C:68](=[O:74])[C@@H:88]([NH:87][S:84]([C:80]3[C:81]([CH3:83])=[CH:82][C:77]([O:76][CH3:75])=[C:78]([CH3:97])[C:79]=3[CH3:96])(=[O:86])=[O:85])[CH2:92][CH:93]([CH3:95])[CH3:94])[C:59](=[O:66])[N:60]3[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]3)=[CH:54][CH:55]=2)[CH:50]=[CH:49][N:48]=1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1C
Reactant: COc1cc(C)c(S(=O)(=O)N[C@@H](CC(C)C)C(=O)O)c(C)c1C
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc2c(N)nccc2c1)C(=O)N1CCCCC1
Agent: CC(C)C[C@H](N)C(=O)O
Agent: Cc1c(C)c(S(=O)(=O)NCC(=O)NC(Cc2ccc3c(N)nccc3c2)C(=O)N2CCCCC2)c(C)c2c1OC(C)(C)CC2
Agent: Cl
Product: COc1cc(C)c(S(=O)(=O)N[C@@H](CC(C)C)C(=O)NC(Cc2ccc3c(N)nccc3c2)C(=O)N2CCCCC2)c(C)c1C

Procedure:
The procedure described for 5c was used. Deprotection of 75 mg of 5a and coupling with 72 mg of (2S)-2-[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]-4-methylpentanoic acid (prepared from L-leucine and 4-methoxy-2,3,6-trimethylphenylsulfonylchloride using the procedure described for 5b) yielded after purification the title compound (65 mg) as a mixture of diastereomers (1:1). 1H-NMR 400 MHz (CD3OD) δ: 0.50 and 0.68 (3H, 2× d, J=7 Hz), 0.61 and 0.79 (3H, 2× d, J=7 Hz), 0.97-1.65 (9H, m), 2.13 (3H, s), 2.54 and 2.56 (3H, 2× s), 2.61 and 2.62 (3H, 2× s), 2.76-3.68 (7H, m), 3.78 and 3.84 (3H, 2× s), 4.98-5.02 and 5.18-5.22 (1H, 2× m), 6.71 (1H, s), 7.16-7.19 (1H, m), 7.53-7.78 (4H, m), 8.29-8.34 (1H, m).
Reaction SMILES: [CH:1]1([CH2:4][C@@H:5]([OH:9])[C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)(=O)C>[CH:1]1([CH2:4][C@@H:5]([OH:9])[C:6]([O:8][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: O=C(O)[C@H](O)CC1CC1
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H](O)CC1CC1
Temperature: 25 °C

Procedure:
A solution of 3.95 g of 3-cyclopropyl-2(R)-hydroxypropionic acid in 50 ml of ethyl acetate was treated with 5.32 ml of triethylamine and 3.8 ml of benzyl bromide. The mixture was stirred and heated under reflux for 3 hours, then allowed to cool to room temperature overnight. The suspension was washed with 2M hydrochloric acid, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate the solvent was evaporated. The residue was purified by flash chromatography on silica gel using hexane/ethyl acetate (2:1) for the elution to give 3.36 g of benzyl 3-cyclopropyl-2(R)-hydroxypropionate in the form of a yellow oil.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C:2]1[CH:9]=[CH:8][C:6]([OH:7])=[C:4]([OH:5])[CH:3]=1.[C:12]1([C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N+]=[N-])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)(=O)C>[C:1]([O:11][CH:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:10])[C:2]1[CH:9]=[CH:8][C:6]([OH:7])=[C:4]([OH:5])[CH:3]=1
Reactant: O=C(O)c1ccc(O)c(O)c1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(OC(c1ccccc1)c1ccccc1)c1ccc(O)c(O)c1
Reaction time: 2 h
Yield: 55.9 %

Procedure:
Ethyl acetate (2.5 ml) was mixed with 50.0 mg of protocatechuic acid and 63.0 mg of diphenyldiazomethane to form a solution. The solution was left over at room temperature for 2 hours. Diphenyldiazomethane (25.8 mg) was added further and the resultant mixture was left over at room temperature for 2 hours. The pale reddish purple-colored reaction solution was concentrated under reduced pressure, and the colorless residue obtained was purified by chromatography on a silica gel column {developer: chloroform - chloroform-methanol (30:1)} to obtain 58.1 mg of the titled compound as a colorless syrup. EIMS: m/z 320 (M+).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:16])=[C:7]([CH:15]=1)[C:8]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[O:9])=[CH2:2].I[C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:28]2[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(N(CCCC)CCCC)CCC>[Pd].CC(N(C)C)=O>[OH:16][C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[CH:2][C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:28]3[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]=3)(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:15][C:7]=1[C:8]([O:10][CH2:11][CH:12]([CH3:13])[CH3:14])=[O:9]
Reactant: Cc1cccnc1NS(=O)(=O)c1ccc(I)cc1
Reactant: C=Cc1ccc(O)c(C(=O)OCC(C)C)c1
Agent: [Pd]
Solvent: CCCCN(CCCC)CCCC
Solvent: CC(=O)N(C)C
Product: Cc1cccnc1NS(=O)(=O)c1ccc(C=Cc2ccc(O)c(C(=O)OCC(C)C)c2)cc1
Yield: 51.4 %

Procedure:
10% Palladium on charcoal (0.5 g) was added to a solution of isobutyl 5-ethenyl-2-hydroxybenzoate (6.6 g, 30 mmol) and 4-iodo-N-(3-methyl-2-pyridinyl)benzenesulfonamide (11.2 g, 30 mmol) in dimethylacetamide (10 ml) and tributylamine (10 ml, 42 mmol) at 110° C. After 90 min. the solution was filtered and diluted with isopropanol (0.3 l) and chilled in a freezer. The product was filtered off, dried and dissolved in boiling formic acid (100 ml). The solution was filtered and water (65 ml) was added. After cooling to refrigerator temperature the product was filtered off and dried to yield 7.2g (51%) product.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][C@@H:18]1[CH2:22][CH2:21][NH:20][CH2:19]1)=[O:16])=[O:12])=O)(C)(C)C.[Br:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[C:34]([F:40])[CH:33]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[NH2:8][C:9]1[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][C@@H:18]1[CH2:22][CH2:21][N:20]([CH2:36][C:35]2[CH:38]=[CH:39][C:32]([Br:31])=[CH:33][C:34]=2[F:40])[CH2:19]1)=[O:16])=[O:12]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCNC1
Reactant: O=Cc1ccc(Br)cc1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCN(Cc2ccc(Br)cc2F)C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a mixture of (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (0.050 mmol), 4-bromo-2 fluorobenzaldehyde (0.15 mmol), methanol (1.5 mL), and acetic acid (0.016 mL) was added NaBH3CN (0.25 mmol) in methanol (0.50 mL). The reaction mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH3OH (5 mL×2). Product was eluted off using 2 N NH3 in CHOH (5 mL) and concentrated. The residue was dissolved in methanol (0.25 mL) and 4 N HCl in dioxane (0.50 mL) was added. The solution was stirred at room temperature for 5 h and concentrated. The residue was dissolved in methanol, loaded onto Varian™0 SCX column, and washed with CH3OH (5 mL×2). Product was eluted off using 2 N NH. in CH3OH (5 mL) and concentrated. The resulting material was dissolved into ethyl acetate (0.5 mL), loaded onto Varian™ Si column, eluted off using ethyl acetate/methanol=5:1 (6 mL), and concentrated to afford (R)-3-[{N-(2-amino-5-trifluoromethylbenzoyl)glycyl}amino]-1-(4-bromo-2-fluorobenzyl)pyrrolidine (Compound No. 2120) (16.0 mg, 31%): The purity was determined by RPLC/MS (99%); ESI/MS m/e 517.0 (M++H, C21H21BrF4N4O2).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)=[CH2:4].[H][H]>[Pd].C(OCC)(=O)C>[F:12][C:2]([F:1])([F:11])[CH:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)[CH3:4]
Reactant: C=C(c1ccncc1)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(c1ccncc1)C(F)(F)F
Yield: 85.7 %

Procedure:
To 20 ml of ethyl acetate were added 1.5 g of 4-[1-(trifluoromethyl)ethenyl]pyridine and 0.15 g of 10% Pd/C, and the mixture was stirred under the hydrogen atmosphere for 7 hours. The mixture was filtered, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography to obtain 1.3 g of 4-(2,2,2-trifluoro-1-methyl-ethyl)pyridine.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:28][C@H:29]([C:37]([CH:39]1[CH:46]2[CH2:47][CH:42]3[CH2:43][CH:44]([CH2:48][C:40]1([NH2:49])[CH2:41]3)[CH2:45]2)=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[C:1]([NH:8][CH2:9][C:10]([NH:28][C@H:29]([C:37]([CH:39]1[CH:46]2[CH2:47][CH:42]3[CH2:43][CH:44]([CH2:48][C:40]1([NH2:49])[CH2:41]3)[CH2:45]2)=[O:38])[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:12])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: N[C@@H](Cc1ccccc1)C(=O)C1C2CC3CC(C2)CC1(N)C3
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)C1C2CC3CC(C2)CC1(N)C3
Temperature: -20 °C
Reaction time: 8 h

Procedure:
A solution of 1.42 g of Boc-glycine and 0.90 ml of N-methylmorpholine in 10 ml of dry methylene chloride under nitrogen is allowed to react with 1.05 ml of isobutylchloroformate at -45° C. The reaction mixture is allowed to warm to -20° C. then recooled to -40° C. To this solution is added 2.38 g of L-phenylalanyl-1-aminoadamantane. The cooling bath is removed and the reaction mixture is allowed to stand overnight at room temperature. The reaction mixture is filtered, diluted with 20 ml of methylene chloride and washed with 10 ml of cold 1 M potassium bisulfate solution followed by washing with 10 ml of cold 2 M potassium carbonate solution and 10 ml of saturated sodium chloride solution. The reaction mixture is dried over sodium sulfate, filtered and concentrated. The product separates as crystals upon addition of ether. The crystalline material is collected to give Boc-glycyl-L-phenylalanyl-1-aminoadamantane. A dry solution of 2.8 g of Boc-glycol-L-phenylalanyl-1-aminoadamantane in 15 ml of methylene chloride under a nitrogen atmosphere at 5° C. is allowed to react with 10 ml of trifluoroacetic acid. The reaction mixture is allowed to stand for 30 minutes at room temperature. The solution is concentrated under reduced pressure then diluted with 10 ml of 5 M potassium carbonate solution and extracted with methylene chloride. The reaction mixture is dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure to give glycyl-L-phenylalanyl-1-aminoadamantane which is represented by the following formula ##STR37##
Reaction SMILES: [CH2:1]([C:4]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].N1C=CN=[CH:12]1.Cl[SiH:17]([CH3:19])[CH3:18]>CN(C=O)C>[CH2:1]([C:4]1([O:10][Si:17]([CH3:19])([CH3:12])[CH3:18])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3]
Reactant: C[SiH](C)Cl
Reactant: C#CCC1(O)CCCCC1
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C#CCC1(O[Si](C)(C)C)CCCCC1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
To a stirred solution of 55.4 g of 1-(2-propyn-1-yl)cyclohexanol [H. Gutmann, et. al., Helv. Chim. Acta, 42, 719 (1959)] and 79 g of imidazole in 240 ml of DMF at 10° C. initially is added 56 ml of chlorodimethylsilane during 10 minutes. The cloudy yellow solution is stirred at room temperature for 26 hours. The resulting mixture is partitioned between 1000 ml of hexane and 400 ml of water at 0°-5° C. The hexane phase is washed successively with 6×200 ml of cold water and 200 ml of brine. The extract is dried over magnesium sulfate, filtered, and evaporated to give 85 g of colorless liquid, i.r. (film): 1240 and 830 cm-1 (trimethylsilyloxy group).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[S:16](Cl)(Cl)(=[O:18])=[O:17]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:16]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)(=[O:18])=[O:17])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: C1CCNCC1
Reactant: Nc1cc(Br)cnc1Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Br)cnc1Cl)N1CCCCC1
Temperature: 40 °C
Yield: 70.5 %

Procedure:
To a 50 ml round-bottom flask equipped with a stir bar and charged with 5-bromo-2-chloropyridin-3-amine (0.245 g, 1.2 mmol) in pyridine (1.5 ml), was added DMAP (0.036 g, 0.30 mmol) and piperidine (0.12 ml, 1.2 mmol). The mixture was chilled to 40° C. in a dry ice/acetone bath. Then sulfuryl chloride (0.10 ml, 1.3 mmol) was added dropwise into the mixture while stirring. After the addition, the ice bath was removed and the mixture was allowed to stir under inert atmosphere overnight. The progress of the reaction was monitored by LC/MS, which showed desired product and consumption of starting material. The mixture was diluted with water (10 ml) and DCM (10 ml). The organic layer was collected by extracting with DCM (3×20 ml). Combined organics, dried over sodium sulfate, filtered and concentrated in vacuo. The crude was dissolved in DCM and purified by ISCO Silica-Gel Chromatography (80 gram column) in a gradient of 5-50% EtOAc/DCM over 20 minutes. The fractions with desired material were combined and concentrated. This gave N-(5-bromo-2-chloropyridin-3-yl)piperidine-1-sulfonamide (0.300 g, 72% yield) as a tan solid. MS (ESI pos. ion) m/z: 355 (MH+). Calc'd exact mass for C10H13BrClN3O2S: 354. 1H NMR (400 MHz, DMSO-d6): 1.42-1.58 (m, 8H), 1.71 (qd, J=5.69, 5.52 Hz, 2H), 3.28 (s, 1H), 8.02 (d, J=2.01 Hz, 1H), 8.38 (d, J=2.51 Hz, 1H).
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][CH:9]=[CH:10][C:11](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1CCN2C(=NCCC2)CC1.Cl.C([SiH](CC)CC)C.[N+:32]([CH3:35])([O-:34])=[O:33]>C(O)(C(F)(F)F)=O.O>[N+:32]([CH2:35][CH:9]1[CH2:8][CH2:7][C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:11][CH2:10]1)([O-:34])=[O:33]
Reactant: O=C1C=CCCc2ccccc21
Reactant: C[N+](=O)[O-]
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: O=[N+]([O-])CC1CCc2ccccc2CC1
Temperature: 55 °C
Yield: 42 %

Procedure:
A solution of 8,9-dihydro-5H-benzo[α][7]annulen-5-one (323 g, 2 mol) in nitromethane (620 ml) was treated with DBU (327 g, 2.1 mol) dropwise at such a rate that the temperature was maintained between 40 and 50° C. After GC analysis showed reaction completion, 3M HCl (600 ml) was added and the resulting mixture was extracted with tert-butyl methyl ether (2×500 ml). The combined organic phases were treated with brine (500 ml), dried over MgSO4, filtered and evaporated to an oil (496 g, 90%). To 347.5 g (1.58 mol) of this material dissolved in TFA (1045 ml) was added triethylsilane (583 ml, 3.65 mol) at such a rate that the temperature of the reaction mixture was maintained between 50 and 55° C. After the addition was complete, the mixture was maintained at 55° C. until GC analysis indicated reaction complete. The mixture was poured onto ice (1500 g) and water (500 ml). The resulting slurry was filtered and washed with cold hexanes (2×150 ml) then dried to give the title compound (139 g, 42%).