Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(C)(C)C.I[CH2:8][O:9][C:10](=[O:16])[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13].[CH3:17][C@@H:18]([OH:37])[C@H:19]1[C:22](=[O:23])[N:21]2[C:24]([C:34]([OH:36])=[O:35])=[C:25]([S:27][C@@H:28]3[CH2:32][S+:31]([O-:33])[CH2:30][CH2:29]3)[S:26][C@H:20]12.C(N(CC)C(C)C)(C)C>CC(C)=O.C(OCC)(=O)C.CCCCCCC.O>[OH:37][C@@H:18]([C@H:19]1[C:22](=[O:23])[N:21]2[C@@H:20]1[S:26][C:25]([S:27][C@H:28]1[CH2:29][CH2:30][S@@:31](=[O:33])[CH2:32]1)=[C:24]2[C:34]([O:36][CH2:8][O:9][C:10](=[O:16])[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:35])[CH3:17]
Reactant: CCC(CC)C(=O)OCI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@H]3CC[S+]([O-])C3)S[C@H]12
Solvent: CCCCCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCC(CC)C(=O)OCOC(=O)C1=C(S[C@H]2CC[S@@](=O)C2)S[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
The semi-crude tert-butyl methyl ether solution of 2-ethyl butyric acid iodomethyl ester from Step 3 was added to a slurry of sulopenem (750 g) in acetone (5.9 L). N,N-Diisopropylethylamine (DIEA) (319 g) in acetone (0.5 L) was added and the mixture was stirred at ambient temperature until reaction completion. Low pyrogen water (6.5 L) and heptane (3.75 L) were added and the phases were separated. The aqueous layer was extracted first with heptane (5 L) and then with ethyl acetate (2×6 L). The ethyl acetate extracts were combined and washed with 5% aqueous sodium thiosulfate (6 L), low pyrogen water (6 L) and 10% aqueous sodium chloride (6 L). The organic extract was treated with activated carbon (75 g) and magnesium sulfate (150 g), then was filtered. The filter cake was washed with ethyl acetate (2×1 L) and the filtrate was evaporated to dryness to provide the crude product (0.8 kg). Ethyl acetate (2.4 L) was added and the solution was heated (45° C.) to achieve dissolution. This solution was then hot-filtered and tert-butyl methyl ether (4.7 L) was added. The resulting slurry was granulated for 10 minutes at 40° C. to 50° C. and was then cooled slowly to less than 10° C. The resulting solid was collected, washed with a 1:2 mixture of ethyl acetate and tert-butyl methyl ether (4×0.5 L) and dried to constant weight under vacuum at up to 50° C. to give 0.57 kg of the desired product (60% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:17][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]12([CH2:28][NH2:29])[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2>C(O)(C)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:16])[CH2:17][NH:29][CH2:28][C:18]23[CH2:27][CH:22]4[CH2:21][CH:20]([CH2:26][CH:24]([CH2:23]4)[CH2:25]2)[CH2:19]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: c1ccc(COc2ccc(C3CO3)cc2)cc1
Solvent: CC(C)O
Product: OC(CNCC12CC3CC(CC(C3)C1)C2)c1ccc(OCc2ccccc2)cc1
Yield: 23.2 %

Procedure:
2-(4-(benzyloxy)phenyl)oxirane (2 g, 8.8 mmol) and (1-adamantylmethyl)amine (1.46 g, 8.8 mol) were dissolved in isopropyl alcohol (30 mL) and heated under reflux overnight. The mixture was concentrated to give the crude product, which was purified by column chromatography to afford 1-(4-(benzyloxy)phenyl)-2-((1-adamantylmethyl)amino)ethanol (0.8 g, 23%). 1H NMR: (CDCl3, 400 MHz) δ=1.51 (m, 6H), 1.60-1.72 (m, 6H), 1.97 (m, 3H), 2.32&2.45 (dd, 2H), 2.64 (m, 1H), 2.73 (m, 1H), 2.94 (m, 1H), 3.40 (brs, 3H), 4.79 (m, 1H), 6.93 (m, 2H), 7.26-7.43 (m, 7H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:18])([F:17])[F:19])=[N:14][N:15]=4)[CH:12]=3)[CH2:6][CH2:5]2)=[CH:24][CH:23]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)cn12
Reactant: COc1ccc(C=O)cc1
Product: COc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4c3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine with 4-methoxybenzaldehyde was carried out according to General Synthetic Method 9. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-methoxyphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:15])[N:5]([CH3:14])[CH:6]=[CH:7][C:8]=1[C:9]([O:11]CC)=[O:10].Cl>C1COCC1.[Li+].[OH-]>[CH3:1][O:2][C:3]1[C:4](=[O:15])[N:5]([CH3:14])[CH:6]=[CH:7][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)c1ccn(C)c(=O)c1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1c(C(=O)O)ccn(C)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of Intermediate 1 (2.2 g, 10 mmol) in THF (3 mL) was added LiOH (10.8 mg, 0.451 mmol) and the reaction mixture was stirred at rt for 16 h. The reaction mixture was acidified to pH=1 using HCl (1M aq., 12.50 mL, 12.50 mmol) concentrated and then evaporated to dryness to provide Intermediate 6 (1.9 g, 10 mmol, 100% yield) as a gray solid. HPLC/MS (Method D) RT=0.42 min, [M+1]+ 184. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.28 (1H, d, J=7.1 Hz), 5.97 (1H, d, J=6.6 Hz), 3.62 (3H, s), 3.31 (3H, s).
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.CC(O)=O.C(O[Na])(C)=O.[Br:19]Br>CO.C1COCC1.C([O-])(=O)C>[Br:19][C:6]1[NH:7][C:8]2[C:4](=[N:3][CH:2]=[N:1][CH:9]=2)[N:5]=1
Reactant: c1ncc2[nH]cnc2n1
Reactant: BrBr
Agent: CC(=O)O[Na]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: Brc1nc2ncncc2[nH]1

Procedure:
A solution of purine in MeOH/THF/acetate buffer (1N in each AcOH and AcONa) was treated with Br2 (1.3-equiv. 1M in CHCl3) at room temperature (r.t.) for 16 h. Evaporation, work-up (EtOAc), drying (MgSO4) and flash chromatography afforded the desired 8-bromopurine.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.[H][H]>[Pd].C(O)(=O)C>[OH:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH2:9][CH2:8]3
Reactant: [H][H]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CO)C2
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1cc2c(c3c1NC(=O)CC3)OC(CO)C2
Yield: 72.8 %

Procedure:
2-Hydroxymethyl-5-methyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (538 mg) was added to acetic acid (AcOH) (11 ml). To the obtained mixture, 10% palladium-on-carbon (323 mg) was added, and the solution was hydrogenated in the atmosphere of hydrogen at 50° C. under atmospheric pressure. After completion of the reaction, the catalyst was filtered off. The solvent was evaporated, and the residue was dissolved in chloroform. The solution was washed with aqueous sodium bicarbonate solution and water in this order, and dried. Subsequently, the solvent was evaporated to obtain 478 mg of a crude. The obtained crude was purified by silica gel column chromatography (eluent:=chloroform:methanol=100:1), to obtain 395 mg of the target compound (72.8%). This substance was recrystallized from a solvent mixture of chloroform-n-hexane. As a result, colorless powdery crystals having a melting point of 172°-173° C. were obtained.
Reaction SMILES: [CH2:1]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[N:6]=1)[CH:2]([CH3:4])[CH3:3].S(Cl)([Cl:29])(=O)=O>C(Cl)Cl>[Cl:29][C:9]1[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[N:6][N:7]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[C:8]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)Cc1cc(-c2ccccc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CC(C)Cc1nn(-c2ccc(S(N)(=O)=O)cc2)c(-c2ccccc2)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the pyrazole prepared in Example 175 (0.15 g, 0.42 mmol) in CH2Cl2 (10 mL) was added an excess of sulfuryl chloride slowly at room temperature. The mixture was stirred at room temperature for 2 hours, quenched with water and the aqueous layer extracted three time with methylene chloride. The combined organic layers were dried over MgSO4 and concentrated to give an oil which was purified by flash chromatography on silica gel using 70:30 hexane/ethyl acetate as eluent to give the desired compound: HRMS m/z 389.0970 (calc'd for C19H20ClN3SO2, 389.0965).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][N:8]([CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:9][C:10](=[O:13])[CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:27])[CH2:7][N:8]([CH:14]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:9][CH:10]([OH:13])[CH2:11][CH3:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC(=O)CN(CC(=O)OC(C)(C)C)C(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(O)CN(CC(=O)OC(C)(C)C)C(c1ccccc1)c1ccccc1
Reaction time: 0.33 h

Procedure:
To a stirred solution of [benzhydryl-(2-oxobutyl)amino]acetic acid tert-butyl ester (7.4 g, 20.1 mmol, 1 eq.) in dry MeOH:THF (100 mL, 1:1) at −23° C., was added CeCl3.7H2O (1.43 g, 3.83 mmol, 0.19 eq.). The reaction mixture was stirred until homogeneous, then NaBH4 (0.57 g, 15.1 mmol, 0.75 eq.) was added slowly (in small portions). The reaction was stirred for additional 20 min, then poured onto brine. This mixture was extracted with DCM, dried over MgSO4, filtered, and concentrated in vacuo to afford [benzhydryl-(2-hydroxybutyl)amino]acetic acid tert-butyl ester in quantative yield. This was used without further purification. ESMS: m/z 370.4 [M+H].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:17]1[CH2:22][CH2:21][CH:20]([N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[CH2:19][CH2:18]1.[Cl:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[OH:37]>>[Cl:30][C:31]1[CH:32]=[C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)[CH2:19][CH2:18]2)[CH:34]=[CH:35][C:36]=1[OH:37]
Reactant: OB(O)c1ccc(O)c(Cl)c1
Reactant: CN1CCN(C2CCN(c3c(C(=O)C4CC4)cnc4ccc(Br)cc34)CC2)CC1
Product: CN1CCN(C2CCN(c3c(C(=O)C4CC4)cnc4ccc(-c5ccc(O)c(Cl)c5)cc34)CC2)CC1
Yield: 57.9 %

Procedure:
Following general procedure D, {6-bromo-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]quinolin-3-yl}(cyclopropyl)methanone (30 mg, 0.065 mmol) was reacted with 3-chloro-4-hydroxyphenylboronic acid (26 mg, 0.150 mmol) to afford the desired product (19 mg, 57%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 8.76 (s, 1H), 8.28 (s, 1H), 8.06-7.98 (m, 2H), 7.71 (d, J=2.3 Hz, 1H), 7.54 (dd, J=8.4, 2.3 Hz, 1H), 7.09-7.03 (m, 1H), 3.55 (d, J=12.8 Hz, 2H), 3.34 (s, 3H), 3.23-3.15 (m, 2H), 2.81-2.50 (m, 8H), 2.35 (s, 3H), 2.12 (d, J=10.6 Hz, 2H), 1.92-1.81 (m, 2H), 1.34-1.28 (m, 2H), 1.27-1.20 (m, 2H); ESI MS m/z 505 [C29H33ClN4O4+H]+; HPLC>99% (AUC), tR=10.01 min.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-])=O)[CH:4]=[C:3]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].C([O-])=O.[NH4+].[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>C(OCC)(=O)C.C(O)C.[Pd]>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][C:20]([F:19])([F:31])[F:32])=[CH:23][CH:24]=2)=[O:30])[CH:4]=[C:3]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cn1C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)cn1C
Temperature: 80 °C
Reaction time: 1 h

Procedure:
304 mg (1.53 mmol) of ethyl 1-methyl-4-nitro-1H-pyrrole-2-carboxylate are initially charged in 6 ml of ethyl acetate/ethanol (1:1), 163 mg (0.15 mmol) of palladium (10% on activated carbon) and 580 mg (9.20 mmol) of ammonium formate are added, and the mixture is stirred at 80° C. for 1 h. After cooling, the mixture is filtered through kieselguhr, the filtercake is rinsed with ethanol and the filtrate is freed from the solvent under reduced pressure. The residue is dissolved in 6 ml of THF, 374 mg (1.84 mmol) of 4-trifluoromethoxyphenyl isocyanate are added and the mixture is stirred at RT for 1 h. The reaction solution is concentrated and the residue is purified by RP-HPLC (acetonitrile/water). This gives a solid.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([F:15])[CH:8]=2)=[CH:5][N:6]=1.[NH2:16][C:17]1[CH:18]=[C:19]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=1>CC(O)C>[C:11]([C:10]1[CH:13]=[CH:14][C:7]([C:4]2[O:3][C:2]([NH:16][C:17]3[CH:18]=[C:19]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=3)=[N:6][CH:5]=2)=[CH:8][C:9]=1[F:15])#[N:12]
Reactant: CS(=O)(=O)Nc1cccc(N)c1
Reactant: N#Cc1ccc(-c2cnc(Cl)o2)cc1F
Solvent: CC(C)O
Product: CS(=O)(=O)Nc1cccc(Nc2ncc(-c3ccc(C#N)c(F)c3)o2)c1
Temperature: 80 °C
Yield: 84.8 %

Procedure:
A mixture of 4-(2-chlorooxazol-5-yl)-2-fluorobenzonitrile 39 (0.225 g, 1.01 mmol) and commercially available N-(3-aminophenyl)methanesulfonamide 6 (0.188 g, 1.01 mmol) in 2-propanol (20 mL) was heated to 80° C. for 18 h with stirring. Reaction mixture was evaporated and crude product was purified using MPLC (Biotage) silica column (Biotage) (Acetone/hexane as an eluent) to provide N-(3-((5-(4-cyano-3-fluorophenyl)oxazol-2-yl)amino)phenyl)methane sulfonamide 40 (0.319 g, 84% yield) as a solid. MS (ES) m/z 373 (M+H+).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:15]([NH:17][C@H:18]([C:24]([NH:26][C@H:27]([C:32]([NH:34][C@H:35]([C:43]([NH:45][C@H:46]([C:50]([NH:52][C@H:53]([C:59]([NH:61][C@H:62]([C:73]([NH:75][C@H:76]([C:81]([NH:83][C@H:84]([C:90]([NH:92][C@H:93]([C:98]([NH:100][C@H:101]([C:105]([OH:107])=[O:106])[C@@H:102]([CH3:104])[OH:103])=[O:99])[CH2:94][C:95](=[O:97])[NH2:96])=[O:91])[CH2:85][CH2:86][S:87]([CH3:89])=O)=[O:82])[CH2:77][CH:78]([CH3:80])[CH3:79])=[O:74])[CH2:63][C:64]1[C:72]2[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=2)[NH:66][CH:65]=1)=[O:60])[CH2:54][CH2:55][C:56](=[O:58])[NH2:57])=[O:51])[CH:47]([CH3:49])[CH3:48])=[O:44])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:33])[CH2:28][C:29](=[O:31])[OH:30])=[O:25])[CH2:19][CH2:20][C:21](=[O:23])[NH2:22])=[O:16])[CH3:14])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8]>C(O)(=O)CS>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:15]([NH:17][C@H:18]([C:24]([NH:26][C@H:27]([C:32]([NH:34][C@H:35]([C:43]([NH:45][C@H:46]([C:50]([NH:52][C@H:53]([C:59]([NH:61][C@H:62]([C:73]([NH:75][C@H:76]([C:81]([NH:83][C@H:84]([C:90]([NH:92][C@H:93]([C:98]([NH:100][C@H:101]([C:105]([OH:107])=[O:106])[C@@H:102]([CH3:104])[OH:103])=[O:99])[CH2:94][C:95](=[O:97])[NH2:96])=[O:91])[CH2:85][CH2:86][S:87][CH3:89])=[O:82])[CH2:77][CH:78]([CH3:80])[CH3:79])=[O:74])[CH2:63][C:64]1[C:72]2[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=2)[NH:66][CH:65]=1)=[O:60])[CH2:54][CH2:55][C:56](=[O:58])[NH2:57])=[O:51])[CH:47]([CH3:48])[CH3:49])=[O:44])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:33])[CH2:28][C:29](=[O:30])[OH:31])=[O:25])[CH2:19][CH2:20][C:21](=[O:23])[NH2:22])=[O:16])[CH3:14])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9]
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCNC(=N)N)C(C)C)C(=O)N[C@@H](CCS(C)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)O)[C@@H](C)O
Agent: O=C(O)CS
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCNC(=N)N)C(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)O)[C@@H](C)O
Reaction time: 24 h

Procedure:
In 2.5 ml of 5% thioglycolic acid-50% aqueous acetic acid was dissolved 25 mg of H-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met(O)-Asn-Thr-OH and reduction was carried out at 45° C. for 24 hours. The reaction mixture was run onto a column (3.4×57 cm) of Sephadex LH-20 and elution was carried out with 30% aqueous acetic acid. The fractions from 200 ml to 240 ml were pooled and lyophilized. Yield 20 mg; Rf3 0.62 (Avicel®); amino acid analysis: Trp 0.74(1); Arg 1.13(1); Asp 2.08(2); Thr 0.95(1); Glu 2.03(2); Ala 1.00(1); Val 0.98(1); Met 0.93(1); Leu 0.99(1); Phe 0.98(1) (peptide content 79%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH:12]([O:14][C:15](=[O:23])[NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][C:10]([CH3:25])([CH3:24])[C:9]=2/[CH:26]=[CH:27]/[C@@H:28]2[O:33][C:32](=[O:34])[CH2:31][C@@H:30]([O:35][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:29]2)=[CH:4][C:3]=1[CH3:53].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH:12]([O:14][C:15](=[O:23])[NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][C:10]([CH3:25])([CH3:24])[C:9]=2/[CH:26]=[CH:27]/[C@@H:28]2[O:33][C:32](=[O:34])[CH2:31][C@@H:30]([OH:35])[CH2:29]2)=[CH:4][C:3]=1[CH3:53]
Reactant: Cc1cc(C2=C(/C=C/[C@H]3C[C@H](O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)CC(=O)O3)C(C)(C)CC(OC(=O)Nc3ccccc3)C2)ccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cc(C2=C(/C=C/[C@H]3C[C@H](O)CC(=O)O3)C(C)(C)CC(OC(=O)Nc3ccccc3)C2)ccc1F
Yield: 74.9 %

Procedure:
In a manner similar to Scheme V, 38 (0.20 gm) was treated with tetrabutylammonium fluoride in THF and acetic acid and, after workup, purified by SiO2 using 1:1 hexanes:EtOAc as eluent and yielded 0.101 g of product. mp 73°-5° C. Anal. C29H32FNO5 : Theory C: 70.57; H: 6.54; N:2.84. Found C.: 70.37; H: 6.94; N: 3.06.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[C:13]([O:16][C:17]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:18]=1[C:19]([OH:21])=O)(=[O:15])[CH3:14].[NH2:27][C@@H:28]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:29]([NH:31][C:32]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=1)=[O:30].ON1C2C=CC=CC=2N=N1.Cl>CN(C)C=O>[C:13]([O:16][C:17]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:18]=1[C:19]([NH:27][C@H:28]([C:29](=[O:30])[NH:31][C:32]1[CH:37]=[C:36]([C:38]([F:40])([F:41])[F:39])[CH:35]=[C:34]([C:42]([F:43])([F:44])[F:45])[CH:33]=1)[CH2:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)=[O:21])(=[O:15])[CH3:14]
Reactant: CC(=O)Oc1ccc(Cl)cc1C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(Cl)cc1C(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.4 %

Procedure:
WSC.HCl (184 mg, 0.96 mmol) was added to a solution of 2-acetoxy-5-chlorobenzoic acid (104 mg, 0.48 mmol), (S)-2-amino-3-phenyl-N-[3,5-bis(trifluoromethyl)phenyl]propionamide (0.20 g, 0.48 mmol) and 1-hydroxybenzotriazole (71.4 mg, 0.53 mmol) in N,N-dimethylformamide (4 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:1→2:1) to give the title compound (141.4 mg, 51.4%) as a white crystal.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.[N:21]1[CH:26]=[N:25][CH:24]=[N:23][C:22]=1[NH2:27]>>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]2[N:8]([C:4]([CH2:3][NH:27][C:22]3[N:23]=[CH:24][N:25]=[CH:26][N:21]=3)=[C:5]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[N:6]=2)[CH:9]=1
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CCl)cc1
Reactant: Nc1ncncn1
Agent: Cl
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CNc2ncncn2)cc1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochloride and 1,3,5-triazin-2-amine. M/e+ 331 for C19H19N6 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 8.51 (s, 1H), 8.24 (s, 1H), 7.94 (s, 1H), 7.65 (d, J=9.1 Hz, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 7.14 (dd, J=9.1, 1.4 Hz, 1H), 5.06 (d, J=5.1 Hz, 2H), 2.39 (s, 3H), 2.32 (s, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH:10]([N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)[C:11](=[O:20])[C:12]([CH:15]1[O:19][CH2:18][CH2:17][O:16]1)([CH3:14])[CH3:13].[BH4-].[Na+].Cl.C(=O)(O)[O-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH:10]([N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)[CH:11]([OH:20])[C:12]([CH:15]1[O:16][CH2:17][CH2:18][O:19]1)([CH3:13])[CH3:14]
Reactant: CC(C)(C(=O)C(Cc1ccc(Cl)cc1Cl)n1cncn1)C1OCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: CC(C)(C1OCCO1)C(O)C(Cc1ccc(Cl)cc1Cl)n1cncn1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
22.9 g (0.06 mol) of 1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4-(dioxolan-2-yl)-4-methyl-pentan-3-one are dissolved in 100 ml of methanol, the solution is cooled to 0° C., and 2.95 g (0.078 mol) of sodium borohydride are added in portions. The mixture is stirred for a further 3 hours at room temperature, 15 ml of concentrated hydrochloric acid are added dropwise, stirring is continued for a further 3 hours and 500 ml of saturated sodium bicarbonate solution are then added. The mixture is extracted with 400 ml of methylene chloride, the phases are separated, the organic phase is wshed with twice 100 ml of water, and the solvent is distilled off. The residue is taken up in 150 ml of diisopropyl ether, and the crystals are filtered off under suction. 1-(2,4-Dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4-(dioxolan-2-yl)-4-methyl-pentan-3-ol is obtained as the B form of melting point 178°-81° C., and after approximately 100 ml of diisopropyl ether have been distilled off, 8.9 g of product are obtained as the A form of melting point 95°-100° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:13](=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:7]2[OH:12].Cl>[Zn].C(O)C>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:7]2[OH:12]
Reactant: CCCCCCCCCCCC(=O)c1ccc2c(Cl)cccc2c1O
Agent: Cl
Agent: [Zn]
Solvent: CCO
Product: CCCCCCCCCCCCc1ccc2c(Cl)cccc2c1O

Procedure:
A solution of 17.4 parts of 1-(5-chloro-1-hydroxynaphthalen-2-yl)-1-dodecanone and 107 parts of 37% hydrochloric acid in 2.5 parts of ethanol was contacted with stirring at reflux during 26 hours, with 40 parts of zinc dust which has been amalgamated by treatment with 3 parts of mercuric chloride and 53 parts of 2.1% hydrochloric acid followed by washing with ethanol. The zinc amalgam was added in small portions throughout the reaction period. Upon cooling, a solid separated. After dissolution of this solid in ethanol, zinc amalgam was filtered, and cooling gave 0.5 parts of starting material which was filtered. Concentration of the filtrate, purification by recrystallization from ethanol, and column chromatography on silica gel using 1-chlorobutane as eluant gave 12 parts of 5-chloro-2-dodecyl-1-naphthalenol, m.p. 68°-70° C.