Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].[Br:4][C:5]1[N:6]=[CH:7][C:8]([NH:11][C:12](=[O:33])[CH:13]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[C:24]([Cl:32])[CH:23]=2)[CH2:14][CH:15]2[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]2)=[N:9][CH:10]=1>CO.N1C=CC=CC=1>[Br:4][C:5]1[N:6]=[CH:7][C:8]([NH:11][C:12](=[O:33])[CH:13]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[C:24]([Cl:32])[CH:23]=2)[CH2:14][CH:15]2[CH2:20][CH2:19][C:18](=[N:2][OH:3])[CH2:17][CH2:16]2)=[N:9][CH:10]=1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCC(=O)CC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(C(CC2CCC(=NO)CC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Temperature: 25 °C
Yield: 80.2 %

Procedure:
A solution of hydroxylamine hydrochloride (13 mg, 0.18 mmol) in methanol (0.5 mL) and pyridine (0.5 mL) was treated with N-(5-bromo-pyrazin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionamide (prepared as in Example 59, 62 mg, 0.12 mmol). The reaction mixture was heated under reflux for 2 h, cooled to 25° C., and concentrated in vacuo to remove methanol. The resulting residue was suspended in ethyl acetate (10 mL), washed with water (1×5 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 3/7 hexanes/ethyl acetate eluted to 8/2 hexanes/ethyl acetate) afforded the N-(5-bromo-pyrazin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-hydroxyimino-cyclohexyl)-propionamide (51 mg, 80%) as a white foam: EI-HRMS m/e calcd for C20H22BrClN4O4S (M+H)+ 529.0307, found 529.0308.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][C:14]1([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:16][CH2:15]1.O.NN>C(O)C>[NH2:3][CH2:12][CH2:13][C:14]1([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)NC1(CCN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC1(CCN)CC1
Yield: 312.1 %

Procedure:
To a solution of tert-butyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]cyclopropylcarbamate (3.3 g, 2.4 mmol) in ethanol (100 mL) was added hydrazine hydrate (5 mL) and the resulting mixture was heated under reflux for 16 hours. The mixture was filtered and washed with diethyl ether. The filtrate was concentrated in vacuo to afford 1.5 g of the pure compound as an orange oil (yield was 75%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[F:24][C:25]1[CH:26]=[C:27]([C:35](O)=[O:36])[C:28]2[O:33][CH2:32][O:31][CH2:30][C:29]=2[CH:34]=1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:35]([C:27]3[C:28]4[O:33][CH2:32][O:31][CH2:30][C:29]=4[CH:34]=[C:25]([F:24])[CH:26]=3)=[O:36])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: O=C(O)c1cc(F)cc2c1OCOC2
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Nc1nc(C(=O)N2[C@H](CNC(=O)c3cc(F)cc4c3OCOC4)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 6-fluoro-4H-benzo[1,3]dioxine-8-carboxylic acid. LC-MS (basic): tR=0.82 min; [M+H]+=513.2.
Reaction SMILES: C(C1C=C(C(C)C)C=C(C(C)C)C=1S(Cl)(=O)=O)(C)C.[Si]([C@@:27]1([OH:68])[C@@H:31]([CH2:32][O:33][Si](C(C)(C)C)(C)C)[O:30][C@@H:29]([N:41]2[CH:48]=[C:47]([CH2:49][O:50][C@H:51]([C:56]3[CH:61]=[C:60]([O:62][CH3:63])[C:59]([I:64])=[CH:58][C:57]=3[N+:65]([O-:67])=[O:66])[C:52]([CH3:55])([CH3:54])[CH3:53])[C:45](=O)[NH:44][C:42]2=[O:43])[CH2:28]1)(C(C)(C)C)(C)C.C([N:71](CC)CC)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[I:64][C:59]1[C:60]([O:62][CH3:63])=[CH:61][C:56]([C@@H:51]([O:50][CH2:49][C:47]2[C:45]([NH2:71])=[N:44][C:42](=[O:43])[N:41]([CH:48]=2)[C@@H:29]2[O:30][C@H:31]([CH2:32][OH:33])[C@@H:27]([OH:68])[CH2:28]2)[C:52]([CH3:54])([CH3:55])[CH3:53])=[C:57]([N+:65]([O-:67])=[O:66])[CH:58]=1
Reactant: COc1cc([C@@H](OCc2cn([C@H]3C[C@@](O)([Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O3)c(=O)[nH]c2=O)C(C)(C)C)c([N+](=O)[O-])cc1I
Reactant: CCN(CC)CC
Agent: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc([C@@H](OCc2cn([C@H]3C[C@H](O)[C@@H](CO)O3)c(=O)nc2N)C(C)(C)C)c([N+](=O)[O-])cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
2,4,6-Triisopropyl benzenesulfonyl chloride (581 mg, 1.92 mmol) was added to a solution of compound 65 (400 mg, 0.48 mmol), DMAP (64 mg, 0.53 mmol), and triethylamine (0.60 mL, 4.32 mmol) in anhydrous CH2Cl2 (15 mL). The mixture was stirred at room temperature overnight under a nitrogen atmosphere, concentrated in vacuo, and the residue was dissolved in a solution of NH3 in 1,4-dioxane (0.5 M, 20 mL). The mixture was transferred into a sealed tube and was heated at 90° C. overnight. The reaction was then cooled to room temperature, concentrated in vacuo, and the residue was dissolved in THF (8.0 mL) followed by addition of n-Bu4NF (333 mg, 1.06 mmol). The mixture was stirred at room temperature for four hours, concentrated in vacuo, and the residue was purified by silica gel column chromatography to yield 5-[(S)-1-(4-iodo-5-methoxy-2-nitrophenyl)-2,2-dimethyl-propyloxy]methyl-2′-deoxycytidine 66 (240 mg, 83% for three steps in total). 1H NMR (400 MHz, MeOD-d4): δ 8.33 (s, 1H, Ph-H), 7.91 (s, 1H, H-6), 7.10 (s, 1H, Ph-H), 6.16 (t, 1H, J=6.4 Hz, H-1′), 5.19 (s, 1H, Ph-CH), 4.41 (d, 1H, J=12.4 Hz, 5-CH2a), 4.33 (m, 1H, H-3′), 4.26 (d, 1H, J=12.4 Hz, 5-CH2b), 3.97 (s, 3H, OCH3), 3.88 (m, 1H, H-4′), 3.70 (m, 2H, H-5′), 2.34 (m, 1H, H-2′a), 2.17 (m, 1H, H-2′b), 0.84 (s, 9H, C(CH3)3).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[O:17]1[C:21]([C:22]2[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:20][N:19]=[CH:18]1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:28]([C:25]2[CH:26]=[CH:27][C:22]([C:21]3[O:17][CH:18]=[N:19][CH:20]=3)=[CH:23][CH:24]=2)(=[O:29])=[O:30])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncc1
Product: O=C(c1ccncc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(-c2cnco2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-Amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 122 mg 4-oxazol-5-yl-benzenesulfonyl chloride. Purification by purification by reversed phase HPLC gave pure product. 1H-NMR (400 MHz, CDCl3): δ 7.21 (dd, H, J=1.5, 4.4 Hz), 7.30 (d,1H, J=2.5 Hz), 7.42 (s,1H), 7.54 (dd,1H, J=2.5, 8.8 Hz 7.61 (d, 2H, J=8.4 Hz), 7.77 (s,1H), 7.78 (d, 2H, J=8.4 Hz), 7.95 (s,1H), 8.69 (d, 2H, J=5.8 Hz), 10.06 (br, 1H). MS: m/z 440.9 (M++1).
Reaction SMILES: [OH:1][C@H:2]([CH2:13][NH:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][C:22]2=[O:27])=[CH:17][CH:16]=1)[CH2:3][NH:4][C:5]([C:7]1[S:8][C:9]([Cl:12])=[CH:10][CH:11]=1)=[O:6].CN1CCC[C:30]1=[O:34].C1N=CN(C(N2C=NC=C2)=O)C=1>C1(C)C=CC=CC=1>[Cl:12][C:9]1[S:8][C:7]([C:5]([NH:4][CH2:3][C@@H:2]2[O:1][C:30](=[O:34])[N:14]([C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][C:22]4=[O:27])=[CH:19][CH:20]=3)[CH2:13]2)=[O:6])=[CH:11][CH:10]=1
Reactant: CN1CCCC1=O
Reactant: O=C(NC[C@H](O)CNc1ccc(N2CCOCC2=O)cc1)c1ccc(Cl)s1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: Cc1ccccc1
Product: O=C(NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1
Temperature: 81.5 °C

Procedure:
25 g of N-{(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}-5-chlorothiophene-2-carboxamide (X) are suspended at from 20 to 25° C. in 250 ml of toluene and admixed with 37.5 ml of 1-methyl-2-pyrrolidone and 11.9 g of N,N-carbonyldiimidazole. The reaction mixture is heated to from 80 to 83° C. for 20 minutes and subsequently heated to 115° C. for one hour. After cooling to 20° C., the precipitated reaction product is filtered off with suction, washed twice with 25 ml each time of water and dried at 60° C. under reduced pressure.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH2:16])=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][CH2:8]2.[CH:17](=O)[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([BH3-])#N.[Na+]>CO.O>[Br:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH2:16])=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]([CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:8]2
Reactant: O=CCCc1ccccc1
Reactant: Nc1c([N+](=O)[O-])cc(Br)c2c1CNCC2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1c([N+](=O)[O-])cc(Br)c2c1CN(CCCc1ccccc1)CC2
Reaction time: 6 h
Yield: 93.3 %

Procedure:
A solution of the product from Example 5 (1 g, 3.24 mmol) and hydrocinnamaldehyde (0.94 g, 7 mmol) in 2:1 MeOH/H2O (50 mL) was treated with sodium cyanoborohydride (0.56 g, 9 mmol) portionwise under nitrogen and stirred for six hours. The solvent was decanted and the semi-solid was dissolved in dichloromethane, dried over magnesium sulfate, filtered and concentrated under vacuum. The crude compound was chromatographed on silica gel (eluted with 25% ethyl acetate in hexane) to give the title compound (1.18 g, 94% yield) as a brown oil.
Reaction SMILES: [NH2:1][CH:2]1[C:13](=[O:14])[N:4]2[C:5]([C:10]([OH:12])=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]12.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.S1C2C=CC=CC=2N=C1S[C:37](=[O:46])[C:38]([C:40]1[N:41]=[C:42]([NH2:45])[S:43][CH:44]=1)=[O:39]>ClCCl>[NH2:45][C:42]1[S:43][CH:44]=[C:40]([C:38](=[O:39])[C:37]([NH:1][CH:2]2[C:13](=[O:14])[N:4]3[C:5]([C:10]([OH:12])=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]23)=[O:46])[N:41]=1
Reactant: Nc1nc(C(=O)C(=O)Sc2nc3ccccc3s2)cs1
Reactant: CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: ClCCl
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Yield: 72 %

Procedure:
4.28 g of 7-amino-3-methylceph-3-em-4-carboxylic acid are suspended under a nitrogen atmosphere in 80 ml of dry dichloromethane, and mixed with 5.4 ml of N,O-bis(trimethylsilyl)acetamide. The preparation is stirred at room temperature until a clear solution is present, and then cooled to -15°. 8.4 g of 2-(2-amino-4-thiazolyl)-2-oxothioacetic-acid-S-benzothiazol-2-ylester are added, and stirred for one hour at -15°, one hour at 0° and then two hours at +20°. The solvent is carefully drawn off on a rotary evaporator, and the oily residue is rubbed with 50 ml of ethanol. The resultant deposit is filtered, washed with ethanol and ether, and vacuum dried at 40°. 5.3 g of the title compound are obtained as a yellow powder.
Reaction SMILES: [O:1]1[C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[C@H:4]([OH:5])[CH:3]=[CH:2]1>O>[O:1]1[C@H:8]([CH2:9][OH:10])[C@H:6]([OH:7])[C@H:4]([OH:5])[CH:3]=[CH:2]1
Reactant: OC[C@H]1OC=C[C@@H](O)[C@@H]1O
Solvent: O
Product: OC[C@H]1OC=C[C@@H](O)[C@H]1O
Yield: 50 %

Procedure:
Glycals have been examined by Lehmann et al. [Brockhaus et al., J. Carbohydr. Res., 53:21 (1977); Lehmann et al., Carbohydr. Res., 58:65 (1977); Lehmann et al., Carbohydr. Res., 58:72 (1977)] in glycosidase-mediated coupling reactions. Those investigators determined that glucal in the presence of emulsin β-glucosidase forms 2-deoxy-Gluβ1,3-glucal in up to 50 percent yield. In addition, incubation of D-galactal in the presence of glycol or water and β-galactosidase formed the corresponding glycosides via addition across the double bond. D-Glucal was reported to react similarly in the presence of β-glucosidase.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:31]=[CH:30][C:9]([O:10][C:11]2[CH:12]=[CH:13][C:14]([NH:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[O:23])=[C:15]([CH:20]=2)[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].[N+:32]([O-])([O-:34])=[O:33].[K+]>FC(F)(F)C(O)=O>[CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:10][C:11]2[CH:12]=[C:13]([N+:32]([O-:34])=[O:33])[C:14]([NH:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[O:23])=[C:15]([CH:20]=2)[C:16]([O:18][CH3:19])=[O:17])=[CH:30][CH:31]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CCS(=O)(=O)c1ccc(Oc2ccc(NC(=O)c3ccccn3)c(C(=O)OC)c2)cc1
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)c1ccc(Oc2cc(C(=O)OC)c(NC(=O)c3ccccn3)c([N+](=O)[O-])c2)cc1
Temperature: 80 °C
Yield: 88.8 %

Procedure:
1.9 g of methyl 5-[4-(ethylsulfonyl)phenoxy]-2-[(2-pyridinylcarbonyl)amino]benzoate was dissolved in 20 ml of trifluoroacetic acid, and 2.2 g of potassium nitrate was added to it and stirred under heat at 80° C. for 2 hours. The reaction liquid was restored to room temperature, trifluoroacetic acid was evaporated away under reduced pressure, the residue was dissolved in chloroform, and aqueous saturated sodium hydrogencarbonate solution was added to it. This was extracted with chloroform, and the organic layer was washed with saturated saline water. After dried, the solvent was evaporated away under reduced pressure, and the residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=2/1 to 1/1) to obtain 1.86 g of the entitled compound as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH3:9])=[CH:4][CH:3]=1.[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1>C(OCC)(=O)C.FC(F)(F)C(O)=O>[O:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]1[O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29][O:24]3)=[CH:12][CH:11]=2)([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH:29]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)=[CH:21][CH:22]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: C1=COCCC1
Reactant: CC(c1ccc(O)cc1)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC(c1ccc(OC2CCCCO2)cc1)(c1ccc(OC2CCCCO2)cc1)c1ccc(OC2CCCCO2)cc1
Reaction time: 8 h
Yield: 77 %

Procedure:
2.53 g (8.26 mmol) of 1,1,1-tris(4-hydroxyphenyl)ethane was dissolved in 20 mL of ethyl acetate in a round bottom flask. 8 mL of 2,3-dihydropyran and 8 drops of trifluoroacetic acid were added to the mixture. After stirring overnight, a white precipitate had formed in the flask. This precipitate was collected by filtration and dissolved in 20 mL of dichloromethane to which was added 8 mL of 2,3-dihydropyran and 6 drops of trifluoroacetic acid. After stiffing for two days, 20 mL of 0.261 N TMAH was added; the organic phase was extracted, washed with water (20 mL) twice, and dried with MgSO4. The solvent was removed in vacuo to yield 2.82 g of THPE-THP as a white powder. Yield: 77%. 1H-NMR (300 MHz, CDCl3) δ (ppm) 1.5-2.0 (18H), 2.09 (3H), 3.60 (3H), 3.92 (3H), 5.37 (3H), 6.91 (6H), 6.98 (6H).
Reaction SMILES: [OH-].[Na+].Cl.[NH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8]1=[O:16].[C:17](OC(=O)C)(=[O:19])[CH3:18].Cl>O.O1CCOCC1>[O:16]=[C:8]1[N:7]([CH2:6][CH2:5][NH:4][C:17](=[O:19])[CH3:18])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9]1
Reactant: NCCn1c(=O)[nH]c2ccccc21
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)NCCn1c(=O)[nH]c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled solution of NaOH (0.41 g, 10 mmoles) in water (5 ml) were simultaneously added 1-(2-aminoethyl)-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (0.7 g, 3.3 mmoles) and a solution of acetic anhydride (0.37 ml, 3.9 mmoles) in dioxane (10 ml). The reaction mixture was stirred for 2 hours at room temperature and then taken to dryness. The residue was dissolved in water, adjusted to pH 4 with 10% aqueous HCl, and extracted with CHCl3. The organic layer was taken to dryness and from the crude residue 0.35 g of the title compound was obtained after crystallization from diethyl ether. M.p. 153° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13]([CH:15]2[CH2:17][CH:16]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:14])[CH:3]=1.[F:24][C@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1>CN1C(=O)CCC1.CS(C)=O.CO>[F:24][C@H:25]1[CH2:29][CH2:28][N:27]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13]([CH:15]3[CH2:17][CH:16]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:14])[CH:3]=2)[CH2:26]1
Reactant: Cc1cc2nc(NC(=O)C3CC3c3ccccc3)cc(Cl)n2n1
Reactant: F[C@H]1CCNC1
Solvent: CS(C)=O
Solvent: CN1CCCC1=O
Solvent: CO
Product: Cc1cc2nc(NC(=O)C3CC3c3ccccc3)cc(N3CC[C@H](F)C3)n2n1
Temperature: 25 °C
Yield: 9.2 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-2-phenylcyclopropanecarboxamide (8C, 200 mg, 1.69 mmol) and (S)-3-fluoropyrrolidine (302 mg, 3.38 mmol) in NMP (5 mL) was stirred at 100° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (35-40% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (59 mg, 44%). 1H NMR (DMSO-d6) δ: 10.87 (s, 1H), 7.26-7.35 (m, 2H), 7.13-7.24 (m, 3H), 6.83 (s, 1H), 5.99 (s, 1H), 5.29-5.58 (m, 1H), 3.72-4.50 (m, 4H), 2.40-2.47 (m, 1H), 2.22-2.36 (m, 5H), 2.15 (br. s., 1H), 1.50 (dt, J=9.2, 4.6 Hz, 1H), 1.35-1.44 (m, 1H). ESI-MS: m/z 380.0 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]([CH2:13][O:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]2)[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]([O-:12])=O)[CH2:6][CH2:5]1.[Li+].[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:26]([NH:33][C:10]([CH:7]1[CH2:6][CH2:5][N:4]([CH2:3][C@@H:2]([OH:1])[CH2:13][O:14][C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][CH:19]=[N:20]3)[CH2:9][CH2:8]1)=[O:12])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCc1ccccc1
Reactant: O=C([O-])C1CCN(C[C@@H](O)COc2cccc3ncccc23)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1ccccc1)C1CCN(C[C@@H](O)COc2cccc3ncccc23)CC1
Reaction time: 18 h

Procedure:
Lithium (R)-1-[2-hydroxy-3-(quinolin-5-yloxy)-propyl]-piperidine-4-carboxylate (32) (100 mg; 0.297 mmol) is dissolved in methylene chloride (3 mL) at ambient temperature. Benzylamine (39) (33 mg; 0.312 mmol), N,N-diisopropylethylamine (85 mg; 0.654 mmol) and PyBOP (186 mg; 0.357 mmol) are added sequentially. The reaction is stirred for 18 hr. at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography with gradient elution (90% ethyl acetate in hexanes, then 50%→100% acetone in hexanes) affording the desired product (40) as an oil. CIMS (NH3Cl): 420 (MH+)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[F:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15](=[O:21])[C:14]([C:22]#[N:23])=[C:13]2[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>N1C=CC=CC=1>[F:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15](=[O:21])[C:14]([C:22]#[N:23])=[C:13]2[N:24]1[CH2:25][CH2:26][N:27]([C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH2:28][CH2:29]1
Reactant: Cn1c(=O)c(C#N)c(N2CCNCC2)c2cc(F)ccc21
Reactant: O=C(Cl)c1cccs1
Solvent: c1ccncc1
Product: Cn1c(=O)c(C#N)c(N2CCN(C(=O)c3cccs3)CC2)c2cc(F)ccc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
2-Thiophene carbonyl chloride (160 μL, 1.5 mmol) was added to a stirred solution of Compound 50 (286 mg, 1.0 mmol) in pyridine (5 mL) under argon at 0° C. The solution was allowed to come to room temperature and further stirred overnight. The solution was poured into ice water and the solids formed were filtered. The solids were washed by excess water, dried, and recrystallized by ethyl acetate to yield 390 mg (98%) of white solids. M.P. 286° C. 1H NMR (DMSO-d6): δ 3.58 (s, 3H), 3.62 (m, 4H), 3.92 (m, 4H), 7.16 (dd, J=3.5, 5.0, 1H), 7.50 (d, J=3.2 Hz, 1H), 7.63–7.68 (m, 3H), 7.80 (d, J=4.8 Hz, 1H). EIMS m/z 397 (M+1). Anal. (C20H17FN4O2S) C, H, N.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[C:10]([N+:20]([O-:22])=[O:21])=[C:11]([O:17]CC)[C:12]([O:14]CC)=[CH:13][C:7]=2[CH:6]=1)=[O:4].Br>C(O)(=O)C>[OH:14][C:12]1[C:11]([OH:17])=[C:10]([N+:20]([O-:22])=[O:21])[C:8]2[S:9][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[CH:13]=1
Reactant: CCOc1cc2cc(C(=O)OC)sc2c([N+](=O)[O-])c1OCC
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)c1cc2cc(O)c(O)c([N+](=O)[O-])c2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5,6-Diethoxy-7-nitro-benzo[b]thiophene-2-carboxylic acid methyl ester (160 mg), hydrobromic acid (8 ml) and acetic acid (8 ml) was refluxed for 6 hours and stirred at room temperature overnight. The solid was filtered and washed with a solution of acetic acid and hydrobromic acid (1:1) and water. The product was recrystallized from acetonitrile.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@:37]2([CH3:38])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:32])[C@H:18]([OH:31])[C:19]#[C:20][C:21]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)([CH3:23])[CH3:22])[CH2:8][C@@H:7]([O:40][C:41](=[O:43])[CH3:42])[CH2:6]1)(=[O:3])[CH3:2].[K].[CH3:45]I>CS(C)=O.C(OCC)(=O)C>[C:1]([O:4][C@@H:5]1[C@@:37]2([CH3:38])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:32])[C@H:18]([O:31][CH3:45])[C:19]#[C:20][C:21]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)([CH3:22])[CH3:23])[CH2:8][C@@H:7]([O:40][C:41](=[O:43])[CH3:42])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)[C@H](O)C#CC(C)(C)OC5CCCCO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Reactant: CI
Agent: [K]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CO[C@H](C#CC(C)(C)OC1CCCCO1)[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)C[C@H](OC(C)=O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 90 %

Procedure:
100 mg of (22S)-1α,3β-diacetoxy-25-tetrahydropyranyloxy-cholest-5-en-23-yn-22-ol (IIIa1) obtained in Example 1 (1) was dissolved in 1.5 ml of dimethylsulfoxide, and after adding thereto 13.2 mg of powderous potassium hydroxyde and 31 μl of methyl iodide, the mixture was stirred for 3.5 hours at room temperature. The reaction solution was diluted with ethyl acetate, washed with water, dried over sodium sulfate, and concentrated. The residue was subjected to silica gel column chromatgraphy (solvent; n-hexane:ethyl acetate=7:1) for purification to give 92 mg of (22S)-1α,3β-diacetoxy-22-methoxy-25-tetrahydropyranyloxy-cholest-5-en-23-yn (IVb1) (yield: 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[Br:18]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]([CH2:9][Br:18])=[CH:7][CH:6]=[CH:5][C:4]=1[O:10][C:11]1[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=1
Reactant: COc1c(C)cccc1Oc1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: COc1c(CBr)cccc1Oc1ccc(Cl)cc1
Yield: 105.7 %

Procedure:
A mixture of 4-chlorophenyl 2-methoxy-3-methylphenyl ether (10.7 g), N-bromosuccinimide (8.3 g) and 2,2'-azobisisobutyronitrile (830 mg) in benzene (70 ml) was refluxed under heating for 2 hrs., and the reaction mixture was treated in a similar manner to that of Example 5-(3) to give oily 4-chlorophenyl 2-methoxy-3-bromomethylphenyl ether (14.9 g).