Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[NH:13][C:5]2[C:6](=[O:12])[NH:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[C:3]=1[Br:14].[BH4-].[Na+]>CN(C=O)C.CO>[Br:1][C:2]1[NH:13][C:5]2[C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[C:3]=1[Br:14]
Reactant: O=C1NCCC(=O)c2c1[nH]c(Br)c2Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C1NCCC(O)c2c1[nH]c(Br)c2Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,3-dibromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-4,8-dione (2.5 g, 7.74 mmol) in a mixture of DMF-MeOH (6 mL) is added NaBH4 (1.47 g, 38.7 mmol). The mixture is stirred at room temperature overnight. It is concentrated and water is added. The mixture is extracted with EtOAc, washed with brine and dried. After the solvent is removed, the residue is subjected to silica gel column chromatography and eluted with CH2Cl2—MeOH to give 2,3-dibromo-4-hydroxy-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one; 1H NMR (DMSO-d6) δ 1.74-1.84 (m, 1H), 2.01-2.10 (m, 1H), 3.00-3.10 (m, 1H), 3.42-3.50 (m, 1H), 4.63-4.68 (m, 1H), 5.06 (d, 1H, J=6.4 Hz), 7.92 (d, 1H, J=4.4 Hz); m/z [M++1] 324.9.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[F:12][C:13]1[CH:14]=[C:15]([CH2:20][CH2:21][CH:22]=O)[CH:16]=[CH:17][C:18]=1[F:19]>>[F:12][C:13]1[CH:14]=[C:15]([CH2:20][CH2:21][CH:22]2[NH:11][CH2:10][CH2:9][N:4]3[C:3]([CH2:1][CH3:2])=[N:7][C:6]([I:8])=[C:5]23)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: CCc1nc(I)cn1CCN
Reactant: O=CCCc1ccc(F)c(F)c1
Product: CCc1nc(I)c2n1CCNC2CCc1ccc(F)c(F)c1

Procedure:
According to the general procedure (GP10), the microwave-assisted Pictet-Spengler reaction (60 W; 100° C.; 8 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (355.2 mg; 1.340 mmol) and 3-(3,4-difluoro-phenyl)-propionaldehyde (228.7 mg; 1.340 mmol) afforded 8-[2-(3,4-difluoro-phenyl)-ethyl]-3-ethyl-1-iodo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine which was Boc-protected and finally purified by HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]([CH3:12])[CH3:11])[C:7]([OH:9])=O)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:37]=[C:38]1[C@@H:44]([NH:45][C:46](=[O:49])[O:47][CH3:48])[CH2:43][CH2:42][C:41](=[O:50])[N:40]2[CH2:51][CH2:52][CH2:53][C@@H:54]([C:55]3[NH:56][C:57]([C:60]4[CH:65]=[CH:64][C:63]([C:66]5[CH:75]=[N:74][C:73]6[C:68](=[CH:69][CH:70]=[C:71]([C:76]7[NH:80][C:79]([C@@H:81]8[CH2:85][CH2:84][CH2:83][NH:82]8)=[N:78][CH:77]=7)[CH:72]=6)[N:67]=5)=[CH:62][CH:61]=4)=[CH:58][N:59]=3)[N:39]12.CCN(C(C)C)C(C)C>CN(C=O)C.[Cl-].[Na+].O.O>[CH3:48][O:47][C:46](=[O:49])[NH:45][C@H:44]1[CH2:43][CH2:42][C:41](=[O:50])[N:40]2[CH2:51][CH2:52][CH2:53][C@@H:54]([C:55]3[NH:56][C:57]([C:60]4[CH:65]=[CH:64][C:63]([C:66]5[CH:75]=[N:74][C:73]6[C:68](=[CH:69][CH:70]=[C:71]([C:76]7[NH:80][C:79]([C@@H:81]8[CH2:85][CH2:84][CH2:83][N:82]8[C:7](=[O:9])[C@@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH:10]([CH3:12])[CH3:11])=[N:78][CH:77]=7)[CH:72]=6)[N:67]=5)=[CH:62][CH:61]=4)=[CH:58][N:59]=3)[N:39]2[C:38]1=[O:37]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: COC(=O)N[C@H]1CCC(=O)N2CCC[C@@H](c3ncc(-c4ccc(-c5cnc6cc(-c7cnc([C@@H]8CCCN8)[nH]7)ccc6n5)cc4)[nH]3)N2C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H]1CCC(=O)N2CCC[C@@H](c3ncc(-c4ccc(-c5cnc6cc(-c7cnc([C@@H]8CCCN8C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]7)ccc6n5)cc4)[nH]3)N2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
In a 10 mL pear-shaped flask, (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (8.35 mg, 47.7 μmol) was combined with DMF (1 ml) (1 ml) to give a colorless solution. HATU (14.5 mg, 38.1 μmol) was added and stirred for 10 min. methyl (4S,7S)-6,10-dioxo-4-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)quinoxalin-2-yl)phenyl)-1H-imidazol-2-yl)octahydro-1H-pyridazino[1,2-a][1,2]diazepin-7-ylcarbamate (21 mg, 31.8 μmol) in 2 ml of DMF and DIPEA (20.5 mg, 27.8 μl, 159 μmol) were added and stirred at room temperature for 1 hr. It was diluted with brine and H2O (10 ml each) and the precipitate was filtered, washed with H2O and hexane, dried on high vacuum at 46° C. to afford ((4S,7S)-4-{5-[4-(6-{2-[(S)-1-((S)-2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-quinoxalin-2-yl)-phenyl]-1H-imidazol-2-yl}-6,10-dioxo-octahydro-pyridazino[1,2-a][1,2]diazepin-7-yl)-carbamic acid methyl ester as a light brownish solid (15 mg, 53.1%). ESI-LRMS m/e calcd for C42H47N11O7, [M+] 817. found 818 [M+H]. 1H NMR (DMSO-d6) δ: 12.34 (br. s., 1H), 12.02 (br. s., 1H), 9.29-9.68 (m, 1H), 8.21-8.52 (m, 4H), 7.71-8.11 (m, 5H), 7.15-7.60 (m, 2H), 5.83 (br. s., 1H), 5.12 (br. s., 1H), 4.46 (br. s., 3H), 4.09 (br. s., 1H), 3.85 (br. s., 3H), 3.56 (d, J=7.5 Hz, 6H), 2.90 (br. s., 3H), 1.56-2.39 (m, 8H), 0.76-1.06 (m, 6H).
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([CH2:12][O:13][C:14]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[C:15]=2[C:16]#[N:17])[CH2:7]1)(=[O:5])[CH2:2][CH2:3][CH3:4]>C(O)(=O)C.C1COCC1.CCOC(C)=O.[Fe]>[NH2:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:14]([O:13][CH2:12][C@H:8]2[CH2:9][CH2:10][CH2:11][N:6]([C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[CH2:7]2)[C:15]=1[C:16]#[N:17]
Reactant: CCCC(=O)N1CCC[C@H](COc2cccc([N+](=O)[O-])c2C#N)C1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)N1CCC[C@H](COc2cccc(N)c2C#N)C1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-((1-butyrylpiperidin-3-yl)methoxy)-6-nitrobenzonitrile (Example 1c, 9.92 g, 32.92 mmol) in acetic acid (60 mL) and THF (60 mL), was added iron powder (5.5 g, 98.76 mmol) at room temperature. The reaction mixture was heated to 70° C. and stirred for 1 hour then cooled to room temperature, diluted with EtOAc, filtered through Celite. The filtrate was concentrated under reduced pressure and then re-dissolved in EtOAc, washed with NaHCO3, water and brine, dried over MgSO4, filtered and evaporated. The residue was crystallized from DCM/EtOAc, to give the title compound as off white solid (9.92 g, 93% for 2 steps). MS 302 (MH+).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][NH:12][O:13][CH3:14].C(N(CC)CC)C.NC1C(N)=NC=CC=1>ClCCl>[CH3:14][O:13][N:12]([CH3:11])[C:8](=[O:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CNOC
Reactant: O=C(Cl)Cc1ccccc1
Agent: Nc1cccnc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-phenylacetyl chloride (commercially available, 4.7 g, 30.5 mmol) in dichloromethane (100 ml) was treated with N,O dimethylhydroxylamine (3.25 g, 33.5 mmol), followed by the addition of triethyl amine (8.5. g 61 mmol) and diaminopyridine (305 mgs). The mixture was stirred at room temperature overnight. The mixture was quenched with water (50 mL) and a saturated solution of ammonium chloride (50 mL). The residue was isolated in a typical aqueous workup and purified by MPLC with 0 to 2% MeOH:CH2Cl2 to give N-methoxy-N-methyl-2-phenylacetamide, (Intermediate 13) (3.5 g 78.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([OH:38])[CH2:17][O:18][C:19]3[C:27]4[CH:26]=[C:25]([C:28]5[O:29][C:30]([C:33](OCC)=[O:34])=[N:31][N:32]=5)[O:24][C:23]=4[CH:22]=[CH:21][CH:20]=3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[BH4-].[Li+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][C@H:16]([OH:38])[CH2:17][O:18][C:19]3[C:27]4[CH:26]=[C:25]([C:28]5[O:29][C:30]([CH2:33][OH:34])=[N:31][N:32]=5)[O:24][C:23]=4[CH:22]=[CH:21][CH:20]=3)[CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)c1nnc(-c2cc3c(OC[C@@H](O)CN4CCC(c5ccc(Cl)c(Cl)c5)CC4)cccc3o2)o1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1nnc(-c2cc3c(OC[C@@H](O)CN4CCC(c5ccc(Cl)c(Cl)c5)CC4)cccc3o2)o1
Temperature: 0 °C
Yield: 99.8 %

Procedure:
(S)-3-(4-(3,4-Dichlorophenyl)piperidino)-1-(2-(5-ethoxycarbonyl-1,3,4-oxadiazol-2-yl)benzo(b)furan-4-yloxy)-2-propanol (1.3 g) obtained in Example 135 was dissolved in THF (20 ml) and lithium borohydride (60 mg) was added with stirring under ice-cooling. The mixture was stirred for 1 hr at room temperature, then poured into ice-water, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give yellow crystals (1.2 g). The crystals were purified by silica gel column chromatography (chloroform/methanol) to give the title compound (100 mg) as pale-yellow crystals, melting point 158–160° C.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[Cl:12][CH2:13][C:14]1[N:15]([CH2:27][C:28]([CH3:31])([OH:30])[CH3:29])[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[CH:18][C:17]=2[N:26]=1.[OH-].[NH4+:33].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:33][C:18]1[C:17]2[N:26]=[C:14]([CH2:13][Cl:12])[N:15]([CH2:27][C:28]([CH3:31])([OH:30])[CH3:29])[C:16]=2[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:19]=1
Reactant: CC(C)(O)Cn1c(CCl)nc2cnc3ccccc3c21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)(O)Cn1c(CCl)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
mCPBA (77% pure, 36.5 g, 163 mmol) was added over 10 minutes to a stirred suspension of 1-[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol (23.6 g, 81.4 mmol) in chloroform (500 mL). The resulting solution was stirred at room temperature for 1.5 hours. Concentrated ammonium hydroxide (200 mL) was added. After 5 minutes, p-toluenesulfonyl chloride (18.6 g, 97.7 mmol) was added in portions. The mixture was stirred at room temperature for 2.3 hours, then was transferred to a separatory funnel. The layers were separated and the aqueous layer was extracted with dichloromethane (2×100 mL, then 3×200 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield a foam. The crude product was purified in portions by chromatography on a HORIZON HPFC system (silica gel, elution with 5% methanol in chloroform followed by gradient elution with 5-15% methanol in chloroform) to yield 9.42 g of 1-[4-amino-2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as a pale yellow solid.
Reaction SMILES: Br.Br[CH:3]([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20]C(OC(C)(C)C)=O)[CH:15]=1)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=O.C(OC(NC1C=C(CC(C2C=CC(OC)=CC=2)=O)C=CN=1)=O)(C)(C)C.[NH2:53][C:54]([NH2:56])=[S:55].C(N(CC)CC)C>C(#N)C>[NH2:20][C:16]1[CH:15]=[C:14]([C:3]2[S:55][C:54]([NH2:56])=[N:53][C:4]=2[C:6]2[CH:7]=[CH:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=2)[CH:19]=[CH:18][N:17]=1
Reactant: COc1ccc(C(=O)C(Br)c2ccnc(NC(=O)OC(C)(C)C)c2)cc1
Reactant: NC(N)=S
Agent: Br
Agent: COc1ccc(C(=O)Cc2ccnc(NC(=O)OC(C)(C)C)c2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(-c2nc(N)sc2-c2ccnc(N)c2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
To a solution of 2-bromo-2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(4-methoxyphenyl)ethanone hydrobromide (synthesized from 2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(4-methoxyphenyl)ethanone (4.5 g, 13 mmol) according to the method described in Reference Example 20) in acetonitrile (40 mL) were added thiourea (1.1 g, 14 mmol) and triethylamine (1.9 mL, 14 mmol), and the mixture was stirred for 2 hours at 80° C. The reaction mixture was cooled to room temperature, then, concentrated. To the residue was added a saturated aqueous sodium hydrogen carbonate solution (200 mL), and the resulting solid was filtrated, and washed with water. To this solid was added 2N-hydrochloric acid (35 mL), and the mixture was stirred for 45 minutes at 100° C. The reaction mixture was cooled to room temperature, then, 8N-sodium hydroxide aqueous solution (10 mL) and aqueous sodium hydrogen carbonate solution (100 mL) were added. The resulted crude crystal was filtrated, and washed with water. This crude crystal was recrystallized from ethanol to obtain a title compound (2.7 g, yield 69%).
Reaction SMILES: [CH3:1][S:2]([N:5]([S:7]([NH:10][C:11]([NH:13]N(S(C)(=O)=O)C)=[O:12])(=[O:9])=[O:8])[CH3:6])(=[O:4])=[O:3].N[C:21]1[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=1>ClC1C=CC=CC=1>[CH3:1][S:2]([N:5]([S:7]([NH:10][C:11]([NH:13][C:21]1[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=1)=[O:12])(=[O:8])=[O:9])[CH3:6])(=[O:3])=[O:4]
Reactant: CN(NC(=O)NS(=O)(=O)N(C)S(C)(=O)=O)S(C)(=O)=O
Reactant: COc1cc(OC)nc(N)n1
Solvent: Clc1ccccc1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)N(C)S(C)(=O)=O)n1
Temperature: 80 °C
Yield: 103.2 %

Procedure:
32.3 g of 1-[(N-methylsulfonyl-N-methylamino)-sulfonyl]-3-(N-methylsulfonyl-N-methylamino)urea are slurried in 500 ml of chlorobenzene, 15.5 g of 2-amino-4,6-di-methoxypyrimidine are added at 80° C. with stirring, and the mixture is heated for 3 hours at 80° C. After cooling to 20° C., the precipitate is filtered off and washed with 100 ml of chlorobenzene. 36.4 g of the desired product are obtained with a purity of 98.1%, corresponding to a yield of 96.8% of theory. The melting point for the product is 183°-185° C. 5.1 g of N-methylmethanesulfonamide are recovered from the filtrate by distillation, corresponding to a yield of 92.7% of theory.
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([O:31][CH3:32])[CH2:22][S:23]([CH2:26][CH2:27][CH2:28][CH2:29][OH:30])(=[O:25])=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>ClCCl>[CH2:1]([O:19][CH2:20][CH:21]([O:31][CH3:32])[CH2:22][S:23]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][S:34]([CH3:33])(=[O:36])=[O:35])(=[O:25])=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCOCC(CS(=O)(=O)CCCCO)OC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOCC(CS(=O)(=O)CCCCOS(C)(=O)=O)OC
Yield: 94.9 %

Procedure:
In 50 ml of dichloromethane is dissolved 2.5 g of 4-[(3-octadecyloxy-2-methoxypropyl)sulfonyl]butanol, to which 0.78 g of methanesulfonyl chloride and 0.95 ml of triethylamine are added dropwise with stirring under ice cooling. After being stirred at room temperature for 40 minutes, the mixture is washed with water, an aqueous sodium bicarbonate solution and water, and dried. The solvent is distilled off under reduced pressure to leave 2.76 g of 4-mesyloxybutyl 3-octadecyloxy-2-methoxypropyl sulfone. This is dissolved in 40 ml of toluene containing 8 g of trimethylamine, and the solution is stirred at room temperature for 40 hours. The reaction mixture is concentrated and reprecipitated from chloroform-acetone to give 2.1 g of the captioned compound.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10](=[O:44])[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH2:42][CH3:43])([C:27]3[CH:32]=[CH:31][C:30](OS(C(F)(F)F)(=O)=O)=[C:29]([CH3:41])[CH:28]=3)[CH2:25][CH3:26])=[CH:20][CH:19]=2)[CH:17]=1.[C:45]([C:47]1([OH:52])[CH2:51][CH2:50][CH2:49][CH2:48]1)#[CH:46]>C(#N)C.[Cu]I>[CH3:8][O:9][C:10](=[O:44])[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([CH2:42][CH3:43])([C:27]3[CH:32]=[CH:31][C:30]([C:46]#[C:45][C:47]4([OH:52])[CH2:51][CH2:50][CH2:49][CH2:48]4)=[C:29]([CH3:41])[CH:28]=3)[CH2:25][CH3:26])=[CH:22][CH:23]=2)[CH:17]=1
Reactant: CCC(CC)(c1ccc(-c2cncc(CC(=O)OC)c2)cc1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Reactant: C#CC1(O)CCCC1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCC(CC)(c1ccc(-c2cncc(CC(=O)OC)c2)cc1)c1ccc(C#CC2(O)CCCC2)c(C)c1
Temperature: 160 °C
Yield: 33.6 %

Procedure:
Triethylamine (0.078 mL, 0.560 mmol), tetrakistriphenylphosphine palladium (43.0 mg, 0.036 mmol) and copper (I) iodide (7.0 mg, 0.037 mmol) were added to a solution of (5-{4-[1-ethyl-1-(3-methyl-4-trifluoromethanesulfonyloxy-phenyl)-propyl]-phenyl}-pyridin-3-yl)-acetic acid methyl ester (Example 144-(2); 0.1 g, 0.186 mmol) and 1-ethynyl-cyclopentanol (61.6 mg, 0.56 mmol) in acetonitrile (0.9 mL), and the mixture was stirred with microwave heating at 160° C. for three minutes. The reaction solution was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the title compound (31.0 mg, 33%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[CH3:21][O:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:24]=1[CH:25]=[O:26].[CH3:33][N:34]([CH3:37])[CH:35]=[S:36]>CCCCCC.C1COCC1>[CH3:33][N:34]([CH3:37])[C:35](=[S:36])[CH:25]([C:24]1[CH:27]=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:23]=1[O:22][CH3:21])[OH:26]
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: CN(C)C=S
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(O)C(=S)N(C)C)c(OC)c1
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 45.7 %

Procedure:
A 110 mL THF solution of lithium diisopropylamide (LDA) (80 mmol) was generated from a 1.6M hexane solution of n-butyllithium (50 mL, 80 mmol) and diisopropylamine (11.2 mL, 80 mmol) at -10° C., then cooled to -78° C. A 50 mL solution of 2,4-dimethoxybenzaldehyde (12 g, 72 mmol) and N,N-dimethylthioformamide (6.8 mL, 80 mmol) was cooled to 0° C. and added to the -78° C. LDA solution at a rate keeping the temperature less than -70° C. The reaction mixture was stirred at -75° C. for 2.5 hours, allowed to warm to 0° C., quenched with saturated aqueous NH4Cl, and extracted with EtOAc three times. The EtOAc extracts were combined, washed with brine, dried (Na2SO4), concentrated, triturated with Et2O/ pet. ether, filtered, and dried in vacuo to give 8.4 g(46% yield) of product: mp 139-140° C.; 1H NMR (CDCl3) d 3.05 (s, 3H, NCH3), 3.50 (s, 3H, NCH3), 3.80 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 5.19-5.21 (d, 1H, J=7 Hz, OH), 5.72-5.74 (d, 1H, J=7 Hz, CH), 6.43-6.47 (m, 2H, ArH), 7.24(s, 1H, ArH); MS(FD) 255 (M+). Anal. Calcd for C12H17NO3S: C, 56.45; H, 6.71; N, 5.49. Found: C, 56.64; H, 6.49; N, 5.59.
Reaction SMILES: O[C:2]1C(=O)C=C(CNS(C2C=CC(C)=CC=2)(=O)=O)OC=1CO.[CH2:23]([O:30][C:31]1[C:32](=[O:50])[CH:33]=[C:34]([CH2:39][NH:40][S:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)(=[O:43])=[O:42])[O:35][C:36]=1[CH2:37][OH:38])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:30][C:31]1[C:32](=[O:50])[CH:33]=[C:34]([CH2:39][NH:40][S:41]([C:44]2[CH:45]=[CH:46][CH:47]=[C:48]([CH3:2])[CH:49]=2)(=[O:43])=[O:42])[O:35][C:36]=1[CH2:37][OH:38])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)NCc2cc(=O)c(O)c(CO)o2)cc1
Reactant: O=c1cc(CNS(=O)(=O)c2ccccc2)oc(CO)c1OCc1ccccc1
Product: Cc1cccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(CO)o2)c1
Yield: 41.35 %

Procedure:
N-(5-Benzyloxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-3-methyl-benzenesulfonamide (10-06) (3.7 g, 41.35%) was synthesized as a white solid from N-(5-hydroxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-4-methyl-benzenesulfonamide (9-06) (7.0 g, 21.54 mmol) following the procedure described for N-(5-benzyloxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (10-01).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([Cl:11])=[CH:4][CH:3]=1.Cl.[CH3:13]O>>[Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:13])=[O:9])[C:5]([Cl:11])=[CH:4][CH:3]=1
Reactant: O=C(O)c1nc(Br)ccc1Cl
Reactant: CO
Agent: Cl
Product: COC(=O)c1nc(Br)ccc1Cl

Procedure:
8.12 g (34.3 mmol) of 6-bromo-3-chloropyridine-2-carboxylic acid are admixed with 50 ml (1.25M; 62.5 mmol) of a solution of hydrogen chloride in methanol. The mixture is heated under reflux for 2 h, in the course of which 20 ml each time (1.25M; 25 mmol) of a solution of hydrogen chloride in methanol are added every 30 min. For workup, the reaction mixture is freed of the solvent on a rotary evaporator and the residue is admixed with diethyl ether and an aqueous sodium hydrogencarbonate solution. After the phase separation, the organic phase is dried; after the filtration, the filtrate is freed of the solvent on a rotary evaporator. The residue obtained is 7.78 g of the product with a purity of approx. 90% by weight.
Reaction SMILES: [C:1]([C:5]1[CH2:9][C:8]([CH:11]=O)([CH3:10])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:20][C:21](=[O:23])[CH3:22])C=CC=CC=1.COC(C)(C)C>ClCCl>[C:1]([C:5]1[CH2:9][C:8]([CH:11]=[CH:20][C:21](=[O:23])[CH3:22])([CH3:10])[O:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(C=O)CC(C(C)(C)C)=NO1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: CC(=O)C=CC1(C)CC(C(C)(C)C)=NO1
Reaction time: 8 h
Yield: 97.8 %

Procedure:
35.0 g (0.21 mole) of 3-tert-butyl-5-formyl-5-methylisoxazoline were added dropwise to a solution of 79 g (0.25 mole) of 1-triphenylphosphoranylidene-2-propanone in 200 ml of dichloromethane. The reaction mixture was kept at 40° C. for 8 hours and then stirred with tert-butyl methyl ether. The residue was filtered off under suction and the filtrate was evaporated down to give 43 g of a yellow oil which slowly crystallized.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl.[F:34][C:35]([F:46])([F:45])[C:36]1[N:40]2[CH2:41][CH2:42][NH:43][CH2:44][C:39]2=[N:38][N:37]=1.ClC1C=CC=CC=1B(O)O.C(OC(C)C)(C)C>O.C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:10][C:11](=[O:13])[N:43]1[CH2:42][CH2:41][N:40]2[C:36]([C:35]([F:46])([F:34])[F:45])=[N:37][N:38]=[C:39]2[CH2:44]1)[CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(CC(=O)O)Cc1cc(F)c(F)cc1F
Reactant: FC(F)(F)c1nnc2n1CCNC2
Agent: Cl
Agent: OB(O)c1ccccc1Cl
Solvent: Cc1ccccc1
Solvent: CC(C)OC(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
25 g of 3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)butyric acid of formula (II) was charged with 200 ml of toluene into a 500 ml 4 necked round bottom flask attached with dean stark apparatus, followed by the addition of 25 ml of Hunig's base at room temperature. Then 25 g of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine HCl was charged and stirred for 5 minutes. 11.5 g of 2-chloro phenyl boronic acid was charged to the reaction mass. After 48 hours of stirring at reflux temperature, the reaction was complete. The reaction mass was cooled to room temperature and 250 ml of water was added to it. The organic layer was separated and washed twice with 125 ml of 1N HCl. The organic layer was separated and washed with 125 ml of water followed by 6% NaHCO3 and finally by 125 ml of water. The organic layer was then separated and the solvent was distilled out under vacuum. The solid obtained was stirred with 125 ml of diisopropyl ether for 2 hours, filtered and then dried under vacuum at 50° C. for 12-15 hours. HPLC was used to obtain the chromatographic purity and chiral purity.