Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1([CH3:26])[C:8](=[O:9])[NH:7][C:6]([C:10]2[N:15]=[C:14]3[S:16][CH:17]=[C:18]([N+:19]([O-:21])=[O:20])[C:13]3=[CH:12][C:11]=2[C:22]([O:24]C)=[O:23])=[N:5]1)([CH3:3])[CH3:2].[OH-].[Na+].O>CO>[CH:1]([C:4]1([CH3:26])[C:8](=[O:9])[NH:7][C:6]([C:10]2[N:15]=[C:14]3[S:16][CH:17]=[C:18]([N+:19]([O-:21])=[O:20])[C:13]3=[CH:12][C:11]=2[C:22]([OH:24])=[O:23])=[N:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc2c([N+](=O)[O-])csc2nc1C1=NC(C)(C(C)C)C(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)C1(C)N=C(c2nc3scc([N+](=O)[O-])c3cc2C(=O)O)NC1=O

Procedure:
The ester (1.0 g, 0.00266 mol) from Example 21 is stirred in 100 mL methanol and 10 mL 10% sodium hydroxide solution for 24 hours. Water (25 mL) is added and the methanol removed in vacuo. Acidification of the aqueous layer gives a brown precipitate which upon filtration and crystallization from methanol-water has mp 260° C.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[C@@H](O)[C@@H]1NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC2C=CC=CC=2)NC(=O)[C@H](CCN)NC(=O)[C@@H](NC([C@@H](N)CCN)=O)CCNC1=O.OS(O)(=O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:115][C:116]([CH3:136])=[CH:117][CH2:118][CH2:119]/[C:120](/[CH3:135])=[CH:121]/[CH2:122][CH2:123]/[C:124](/[CH3:134])=[CH:125]/[CH2:126][S:127][CH2:128][C@H:129]([NH2:133])[C:130]([OH:132])=[O:131]>C(Cl)Cl>[CH:10]([C@@H:9]([C:13](=[O:15])[NH:133][C@H:129]([C:130]([OH:132])=[O:131])[CH2:128][S:127][CH2:126]/[CH:125]=[C:124](\[CH3:134])/[CH2:123][CH2:122]/[CH:121]=[C:120](\[CH3:135])/[CH2:119][CH2:118][CH:117]=[C:116]([CH3:136])[CH3:115])[NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:11])[CH3:12]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Agent: CC(C)C[C@@H]1NC(=O)[C@@H](Cc2ccccc2)NC(=O)[C@H](CCN)NC(=O)[C@@H](NC(=O)[C@@H](N)CCN)CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 100 mL round bottom flask, N-Boc-L-valine (1.0 mmol), coupling reagent (520 mg of PBOP or 380 mg of HATU, 1 mmol) and N,N-diisopropyl-ethyl-amine (650 mg, 5 mmol) were mixed in CH2Cl2 (10 mL). The reaction mixture was stirred at room temperature for 30 minutes. S-trans, trans-farnesyl-L-cysteine (325 mg, 1 mmol) was added to the reaction mixture and stirred at room temperature overnight. CH2Cl2 was removed by rotary evaporation. The resulting residue was dissolved in ethyl acetate (50 mL). The organic solution was washed with an NH4Cl saturated solution (50 mL), dried over Na2SO4, and concentrated to afford a crude mixture. The crude mixture was purified by preparative HPLC (276 mg, 53%) to yield Compound N-9. 1H-NMR (500 MHz, CD3OD): δ 0.95 (d, J=6.5 Hz, 3H), 0.99 (d, J=6.5 Hz, 3H), 1.21 (m, 1H), 1.47 (s, 9H), 1.62 (bs, 6H), 1.69 (s, 3H), 1.71 (s, 3H), 1.99 (t, J=7.5 Hz, 2H), 2.05-2.15 (m, 8H), 2.78 (dd, J=8.5, 14.0, 1H), 3.00 (dd, J=4.5, 14.0 Hz, 1H), 3.16 (dd, J=7.5, 13.2 Hz, 1H), 3.27 (dd, J=8.4, 13.2 Hz, 1H), 3.95 (d, J=6.5 Hz, 1H), 4.61 (dd, J=4.8, 8.0 Hz, 1H), 5.10-5.14 (m, 2H), 5.51 (t, J=7.4 Hz, 1H). 13C-NMR (125 MHz, CDCl3): δ 16.2, 16.3, 17.8, 18.4, 19.8, 25.9, 27.4, 27.8, 28.8, 30.3, 32.2, 33.5, 40.8, 40.9, 53.3, 61.5, 80.6, 121.6, 125.2, 125.5, 132.1, 136.3, 140.5, 157.9, 173.6, 174.4; ES-MS: mass calcd for Chemical Formula: C28H48N2O5S 524.7. Found (M+Na) m/z 547.4.
Reaction SMILES: [CH3:1][C:2]1[NH:3][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:7])[CH:6]=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH3:25][O:26][C:27]1[CH:28]=[CH:29][C:30]2[S:34][C:33](SC)=[N+:32]([CH3:37])[C:31]=2[CH:38]=1.C(N(CC)CC)C>CO>[CH3:25][O:26][C:27]1[CH:28]=[CH:29][C:30]2[S:34](=[C:6]3[C:5](=[O:7])[N:4]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[NH:3][CH:2]3[CH3:1])[CH2:33][N:32]([CH3:37])[C:31]=2[CH:38]=1
Reactant: Cc1cc(=O)n(-c2ccccc2)[nH]1
Reactant: COc1ccc2sc(SC)[n+](C)c2c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)N(C)CS2=C1C(=O)N(c2ccccc2)NC1C
Reaction time: 3.5 h

Procedure:
3-Methyl-1-phenylpyrazolin-5-one (1.74 g, 0.01 mol) was mixed with 3.97 g (0.01 mol) 5-methoxy-2-methylthio-3-methylbenzothiazolium tosylate in 25 ml methanol. Triethylamine (1.01 g, 0.01 mol) was added. The mixture was stirred for 3.5 hours, then filtered and washed with methanol. After drying the yield was 276 g (79%), mp 155°-156° C., λmax=386 (ε=25,000).
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:57]=[CH:56][C:12]2[NH:13][C:14]([CH2:16][CH2:17][CH:18]3[CH2:21][CH:20]([N:22]([CH2:24][C@@H:25]4[C@H:29]5[O:30]C(C)(C)[O:32][C@H:28]5[C@H:27]([N:35]5[C:39]6[N:40]=[CH:41][N:42]=[C:43]([NH:44]CC7C=CC(OC)=CC=7OC)[C:38]=6[CH:37]=[CH:36]5)[CH2:26]4)[CH3:23])[CH2:19]3)=[N:15][C:11]=2[CH:10]=1.C([SiH](CC)CC)C>O>[NH2:44][C:43]1[C:38]2[CH:37]=[CH:36][N:35]([C@@H:27]3[CH2:26][C@H:25]([CH2:24][N:22]([CH:20]4[CH2:19][CH:18]([CH2:17][CH2:16][C:14]5[NH:13][C:12]6[CH:56]=[CH:57][C:9]([Br:8])=[CH:10][C:11]=6[N:15]=5)[CH2:21]4)[CH3:23])[C@@H:29]([OH:30])[C@H:28]3[OH:32])[C:39]=2[N:40]=[CH:41][N:42]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCc4nc5cc(Br)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN(C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@H](O)[C@@H]1O)C1CC(CCc2nc3cc(Br)ccc3[nH]2)C1
Reaction time: 1 h
Yield: 27.1 %

Procedure:
Trifluoroacetic Acid (20 ml) added to a mixture of Water (2 ml) and 7-((3aS,4R,6R,6aR)-6-(((3-(2-(5-bromo-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(methyl)amino)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.9 g, 1 mmol) at RT. The reaction mixture was stirred for one hour, Triethylsilane (0.39 ml, 2.4 mmol) was added. The volatiles were removed in vacuo and resulting residue was purified twice by flash chromatography (DCM/7N NH3 in MeOH 87:13). The residue was taken up in MeOH/H2O (5:0.5 ml) and K2CO3 (100 mg) added. The mixture was stirred for 1 hour, then concentrated and purified by flash chromatography (DCM/7N NH3 in MeOH 87:13) to give the desired product (0.15 g) as an off-white foam/gum. cyclobutyl)(methyl)amino)methyl)cyclopentane-1,2-diol (0.15 g; 20%) as an off-white foam/gum. MS (ESI+) for C26H32BrN7O2 m/z 554.1 [M+H]−; MS (ESI−) C26H32BrN7O2 m/z 552.1 [M−H]−; HPLC purity >90% (ret. time, 2.298 min.) 1H NMR (400 MHz, d4-MeOH) δH 8.080 (s, 1H), 7.652 (s, 1H), 7.425-7.403 (m, 1H), 7.342-7.7.312 (m, 1H), 7.232-7.217 (m, 1H), 6.620-6.611 (d, J=3.6 Hz, 1H), 4.358-4.318 (m, 1H), 3.928-3.888 (m, 1H), 3.099-3.039 (m, 0.5H (methine of trans isomer)), 2.898-2.829 (m, 2H), 2.777-2.726 (m, 0.5H (methine of cis isomer)), 2.580-2.529 (m, 1H), 2.453-2.397 (m, 2H), 2.307-2.141 (7H), 2.068-2.017 (m, 1H), 1.955-1.891 (m, 3H), 1.695-1.506 (m, 2H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[OH:7][C:8]1[CH:12]([CH:13]2[CH2:18][CH2:17][N:16]([O:19][CH3:20])[CH2:15][CH2:14]2)[NH:11][C:10](=[O:21])[C:9]=1[C:22]1[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=1[CH3:30].CCN(CC)CC>CN(C1C=CN=CC=1)C.CC(C)=O>[CH3:20][O:19][N:16]1[CH2:17][CH2:18][CH:13]([CH:12]2[C:8]([O:7][C:2](=[O:3])[O:4][CH2:5][CH3:6])=[C:9]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=3[CH3:30])[C:10](=[O:21])[NH:11]2)[CH2:14][CH2:15]1
Reactant: CON1CCC(C2NC(=O)C(c3c(C)cc(C)cc3C)=C2O)CC1
Reactant: CCOC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)OC1=C(c2c(C)cc(C)cc2C)C(=O)NC1C1CCN(OC)CC1
Reaction time: 0.25 h

Procedure:
Ethyl chloroformate (216 mg, 2 mmol) was added dropwise to a mixture of 4-hydroxy-5-(1-methoxy-piperidin-4-yl)-3-(2,4,6-trimethyl-phenyl)-1,5-dihydro-pyrrol-2-one (400 mg, 1.2 mmol), Et3N (606 mg, 6 mmol) and DMAP (60 mg, 0.5 mmol) in acetone (20 ml). The mixture was stirred for 15 min and concentrated under vacuum to dryness. The residue was purified by column chromatography on silica gel. Yield: 260 mg of carbonic acid ethyl ester 2-(1-methoxy-piperidin-4-yl)-5-oxo-4-(2,4,6-trimethyl-phenyl)-2,5-dihydro-1H-pyrrol-3-yl ester (title compound P1.12) as a solid, mp 154-155° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7].[F:10][CH:11]([F:13])I.CN(C=O)C.[H-].[Na+]>O>[F:10][CH:11]([F:13])[N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc[nH]1
Reactant: FC(F)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccn1C(F)F

Procedure:
Was prepared from stirred a mixture of methyl 1H-pyrrole-2-carboxylate (3.04 g, 23.5 mmol), difluoroiodomethane (4.4 g, 24.7 mmol) and DMF (40 ml). Sodium hydride (1.41 g, 35.2 mmol) was added in portions during 30 minutes. The mixture was stirred for additional 15 minutes. Water (50 ml) was added and the mixture was extracted with dichloromethane. The mixture was purified by silica gel chromatography, using dichloromethane as solvent. The product was dried and evaporated. Yield 3.21 g (78%).
Reaction SMILES: C(OC([CH:11]([NH2:27])[CH2:12][C:13]1[NH:14][C:15](=[O:26])[C:16]2[C:21]([CH3:22])=[C:20]([C:23]([OH:25])=[O:24])[S:19][C:17]=2[N:18]=1)=O)C1C=CC=CC=1.[BrH:28]>>[BrH:28].[NH2:27][CH2:11][CH2:12][C:13]1[NH:14][C:15](=[O:26])[C:16]2[C:21]([CH3:22])=[C:20]([C:23]([OH:25])=[O:24])[S:19][C:17]=2[N:18]=1
Reactant: Cc1c(C(=O)O)sc2nc(CC(N)C(=O)OCc3ccccc3)[nH]c(=O)c12
Agent: Br
Product: Cc1c(C(=O)O)sc2nc(CCN)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 387 mg of so obtained 2-(2-benzyloxycarbonyl-aminoethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid and 4.5 mL of hydrobromic acid was stirred at room temperature for 3 hours, and thereafter the solvent was distilled off under reduced pressure to provide 410 mg (quantitative) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[N:30]=[CH:31][C:32]([CH2:35][C:36]#[N:37])=[N:33][CH:34]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:28][C:29]2[CH:34]=[N:33][C:32]([CH2:35][C:36]#[N:37])=[CH:31][N:30]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Reactant: N#CCc1cnc(N)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2cnc(CC#N)cn2)cc1Cl
Temperature: 0 °C
Yield: 58.4 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 33, 663.1 mg, 2.004 mmol) in methylene chloride (10 mL) was treated with N,N-dimethylformamide (2 drops) and then cooled to 0° C. The reaction mixture was then treated with oxalyl chloride (357 μL, 4.009 mmol). The reaction mixture was stirred at 0° C. and then warmed to 25° C. where it was stirred for 1.5 h. At this time, the reaction mixture was concentrated in vacuo. The yellow slurry was dissolved in methylene chloride (10 mL) and then cooled to 0° C. To this solution was added a mixture of (5-amino-pyrazin-2-yl)-acetonitrile (268.9 mg, 2.004 mmol) and pyridine (324 μL, 4.009 mmol) in methylene chloride (10 mL). The reaction mixture was stirred at 0° C. for 30 min and then warmed to 25° C. where it was stirred for 16 h. The reaction mixture was then diluted with methylene chloride (100 mL) and water (50 mL). The organic layer was washed with a 1N aqueous hydrochloric acid solution (50 mL), a saturated aqueous sodium bicarbonate solution (50 mL), and a saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40L, Silica, 1/9 ethyl acetate/methylene chloride) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-cyanomethyl-pyrazin-2-yl)-3-cyclopentyl-propionamide (523.4 mg, 58%) as a white foam: mp 79–82° C. (foam to gel); (ES)+-HRMS m/e calcd for C21H23ClN4O3S (M+H)+ 447.1252, found 447.1255.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[OH:28]>>[F:21][C:22]1[CH:23]=[C:24]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])[CH:25]=[CH:26][C:27]=1[OH:28]
Reactant: OB(O)c1ccc(O)c(F)c1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(O)c(F)c3)ccn2c1=O
Yield: 76.1 %

Procedure:
Methyl 8-(3-fluoro-4-hydroxyphenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and (3-fluoro-4-hydroxyphenyl)boronic acid (64.1 mg, 0.41 mmol). The residue was rinsed with DCM and dried in a vacuum stove to afford the title compound as a yellow solid (95 mg, 76%).
Reaction SMILES: C(O[C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)(=O)C.S(=O)(=O)(O)O.[OH:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[C:26]([Br:31])[CH:25]=[CH:24]2>CCCCCCC>[C:5]12([C:30]3[CH:29]=[C:28]4[C:23]([CH:24]=[CH:25][C:26]([Br:31])=[CH:27]4)=[CH:22][C:21]=3[OH:20])[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2
Reactant: CC(=O)OC12CC3CC(CC(C3)C1)C2
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: O=S(=O)(O)O
Solvent: CCCCCCC
Product: Oc1cc2ccc(Br)cc2cc1C12CC3CC(CC(C3)C1)C2

Procedure:
In a 100 ml flask, under a nitrogen atmosphere, are placed 2 g of 1-acetoxyadamantane and 20 ml of n-heptane, and 0.5 g of concentrated sulfuric acid is introduced drop by drop. At a temperature of about 22.C, 2.3 of 6-hydroxy-2-bromonaphthalene are added slowly and the mixture is left in vigorous agitation. The solvent is eliminated by filtration and the solid residue in suspension in the water is collected. The residue is filtered and then washed until neutrality is obtained. The resulting reddish solid is washed again with hexane until a colorless filtrate is obtained. After drying in a vacuum oven for 24 hours at 30 C one obtains a raw product which is chromatographed with a silica column using an ethyl acetate and hexane mixture of 1:9 as the eluent. After evaporation of the solvents, 1.3 g of desired raw product were obtained (Melting point: 218°-224° C.).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]=[CH:2]2.[CH2:8]([O:12][CH3:13])[CH:9]1[O:11][CH2:10]1.[CH2:14]1[CH2:18]O[CH2:16][CH2:15]1>C1(C)C=CC=CC=1>[CH2:18]([C:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]=[CH:2]2)[CH2:14][CH2:15][CH3:16].[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]=[CH:2]2.[CH2:8]([O:12][CH3:13])[CH:9]1[O:11][CH2:10]1
Reactant: C1CCOC1
Agent: C1=CC2CCC1C2
Agent: COCC1CO1
Solvent: Cc1ccccc1
Product: CCCCC12C=CC(CC1)C2
Temperature: 80 °C

Procedure:
BuNB (10.52 g, 0.07 mol), Methyl Glycidyl Ether Norbornene (AGENB, CAS 3188-75-8) (5.41 g, 0.03 mol), toluene (58.0 g) were added to a serum bottle in the drybox. The solution was stirred at 80° C. in an oil bath. To this solution were added a toluene solution (5 g) of (η6-toluene)Ni(C6F5)2 (0.69 g, 0.0014 mol). After the addition, the resulting mixture was maintained at room temperature for 4 hours. A toluene solution (87.0 g) was added to the reaction solution. The copolymer was precipitated by adding methanol drop wise into the vigorously stirred reaction mixture. The precipitated copolymer was collected by filtration and dried in an oven at 60° C. under vacuum. After drying, 12.74 g was obtained (80%). The molecular weight of the copolymer was determined by GPC in THF solvent (polystyrene standard) to be Mw=75,000 and Mn=30,000. The composition of the copolymer was determined by 1H-NMR to be (78/22) BuNB/AGENB copolymer. The refractive indices of this polymer were measured by prism coupling method and determined to be 1.5162 in TE mode and 1.5157 in TM mode at a wavelength of 633 nm. The dried copolymer was dissolved in sufficient toluene to result in a 30 wt % copolymer solution.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][N:3]=1.[CH3:10]I.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][O:9][CH3:10])=[CH:4][N:3]=1
Reactant: OCc1cnc(Cl)nc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1cnc(Cl)nc1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 66.1 %

Procedure:
To a solution of 2-chloro-5-hydroxymethyl-pyrimidine (9.0 g, 62 mmol) in 70 ml of anhydrous DMF was added methyl iodide (6 eq. 370 mmol, 23 ml). The mixture was cooled to 0° C., then NaH (2.61 g, 1.05 eq.) was added in portions over 5 mins. The resulting mixture was stirred 25 min. at 0° C., then 25 min. at rt. The reaction mixture was then cooled in ice bath, and quenched by addition of saturated NH4Cl aq. solution (200 ml), extracted with ether (150 ml×3). The combined organic layers were washed by brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by ISCO column (330 g of silica gel) using ethyl acetate in hexane (0-90% ethyl acetate, 2500 ml, then 1000 ml of ethyl acetate) to give 6.5 g (66%) of the title compound: MS (ESI) m/z 159.2 (M+H); 1H NMR (500 MHz, CDCl3) δ 8.60 (s, 2H), 4.48 (s, 2H), 3.45 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:18]4[CH2:19][C:20]5[S:21][CH:22]=[CH:23][C:24]=5[C:17]=4[N:16](COCC[Si](C)(C)C)[N:15]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl>CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[C:18]4[CH2:19][C:20]5[S:21][CH:22]=[CH:23][C:24]=5[C:17]=4[NH:16][N:15]=3)=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc(-c3nn(COCC[Si](C)(C)C)c4c3Cc3sccc3-4)cc2)CC1
Agent: Cl
Solvent: CO
Product: CN1CCN(c2ccc(-c3n[nH]c4c3Cc3sccc3-4)cc2)CC1
Temperature: 100 °C
Yield: 74.5 %

Procedure:
6-[4-(4-Methyl-piperazin-1-yl)-phenyl]-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.22 g, 0.47 mmol) was dissolved in MeOH and treated with concentrated HCl (0.14 mL, 4.7 mmol). The reaction mixture was heated at 100° C. for 4 hr. The solution was cooled to room temperature and the resultant precipitate was filtered, washed with MeOH and concentrated under reduced pressure to provide the corresponding 6-[4-(4-Methyl-piperazin-1-yl)-phenyl]-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.1 g, 0.35 mmol) as brown solid in 74% yield.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@@H:27]([CH2:28][OH:29])[CH2:26][CH2:25][C:24]4=[O:30])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[H-].[Na+].O1CCC[CH2:34]1.S(C1C=CC(C)=CC=1)(OC)(=O)=O>O>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[C@@H:27]([CH2:28][O:29][CH3:34])[CH2:26][CH2:25][C:24]4=[O:30])=[CH:21][CH:22]=3)=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CC[C@@H]4CO)cc3)CC2)c(C)c1
Reactant: C1CCOC1
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC[C@H]1CCC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of (R)-1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-5-hydroxymethylpyrrolidin-2-one (200 mg) described in Example 284 and sodium hydride (22 mg) was added tetrahydrofuran, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added methyl tosylate (74 μL), and the mixture was further stirred at room temperature for 2 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give (R)-1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-5-methoxymethylpyrrolidin-2-one. The obtained (R)-1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-5-methoxymethylpyrrolidin-2-one was dissolved in ethyl acetate, 4N hydrogen chloride/ethyl acetate was added, and the precipitate was collected by filtration to give the title compound (113 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[CH3:14])[CH:7]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C.CCOC(C)=O>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:2]2[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([N:8]3[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]3[CH3:14])[CH:7]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Cc1ccc(C)n1-c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C)n1-c1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 30 %

Procedure:
To a stirred solution of 1-(5-chloro-2-nitro-phenyl)-2,5-dimethyl-1H-pyrrole (73 mg, 0.29 mmol, as prepared in the previous step) in DMF (2 mL) was added piperazine-1-carboxylic acid tert-butyl ester (542 mg, 2.9 mmol) and the result was heated to 90° C. for 18 h. The reaction a diluted with EtOAc (50 mL), washed with H2O (2×25 mL), dried (Na2SO4) and concentrated in vacuo. The residue was chromtographed on a SPE column (5 g, SiO2) to afford 35 mg (30%) of the title compound as a brown solid. 1H-NMR (CDCl3; 400 MHz): δ 8.13 (d, 1H, J=9.3 Hz), 6.91-6.88 (m, 1H), 6.66 (s, 1H), 5.93 (s, 2H), 3.63-3.60 (m, 4H), 3.42-3.40 (m, 4H), 1.97 (s, 6H), 1.48 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[C:16]1[NH:17][C:18]2[C:23]([C:24]=1[CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[CH:22][CH:21]=[C:20]([C:31]([O:33][CH3:34])=[O:32])[CH:19]=2.C([O-])(=O)C.[Na+].C(O)(=O)C.[Cl:44][CH2:45][C:46](Cl)=[O:47]>O1CCCC1.O>[CH2:9]([O:8][C:6]1[CH:5]=[CH:4][C:3]([C:16]2[NH:17][C:18]3[C:23]([C:24]=2[CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:22][CH:21]=[C:20]([C:31]([O:33][CH3:34])=[O:32])[CH:19]=3)=[C:2]([NH:1][C:46](=[O:47])[CH2:45][Cl:44])[CH:7]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OCc4ccccc4)cc3N)[nH]c2c1
Reactant: O=C(Cl)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OCc4ccccc4)cc3NC(=O)CCl)[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.4 %

Procedure:
To a suspension of methyl 2-(2-amino-4-benzyloxyphenyl)-3-cyclohexyl-1H-indole-6-carboxylate (6.17 g, 13.5 mmol), sodium acetate (1.22 g, 14.9 mmol) and acetic acid (0.86 ml, 14.9 mmol) in tetrahydrofuran (62 ml) was added dropwise chloroacetyl chloride (1.19 ml, 14.9 mmol), and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and methanol was added. The precipitated solid was collected by filtration, washed with methanol and dried in vacuo to give methyl 2-[4-benzyloxy-2-(2-chloroacetylamino)phenyl]-3-cyclohexyl-1H-indole-6-carboxylate (3.90 g, yield 54%).