Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=3)[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27].C(#N)C.I.C(=O)(O)[O-].[Na+]>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([N:9]2[CH2:10][CH2:11][C:3]3[C:2]([NH:27][C:26]4[CH:28]=[CH:29][CH:30]=[C:24]([O:23][CH3:22])[CH:25]=4)=[N:7][CH:6]=[N:5][C:4]=3[CH2:8]2)=[N:13][CH:14]=1
Reactant: FC(F)(F)c1ccc(N2CCc3c(Cl)ncnc3C2)nc1
Reactant: COc1cccc(N)c1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1cccc(Nc2ncnc3c2CCN(c2ccc(C(F)(F)F)cn2)C3)c1
Temperature: 160 °C
Yield: 443.9 %

Procedure:
A mixture of 4-chloro-7-(5-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (0.035 g, 0.00011 mol), 3-methoxyaniline (0.018 mL, 0.00016 mol) in acetonitrile (0.5 mL, 0.01 mol) and 47% HI (0.05 mL, 0.0007 mol) was heated at 160° C. for 20 minutes in in a sealed tube via microwave. After cooling to r.t., the mixture was poured into saturated aqueous sodium bicarbonate (5 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with brine and dried over magnesium sulfate. Concentrated to leave a brown solid. Residue was purified by flash chromatography over silica gel (ethyl acetate/hexane gradient 0 to 100%) to give 0.196 g of a white foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:12][CH2:13][O:14][CH3:15])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:16][C:17]([CH3:24])([CH3:23])[CH2:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4]([C:6]1([CH2:12][CH2:13][O:14][CH3:15])[CH2:7][CH2:8][N:9]([S:19]([CH2:18][C:17]([CH3:24])([CH3:23])[CH3:16])(=[O:21])=[O:20])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: CC(C)(C)CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)CC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.72 g) in methylene chloride (40 ml) was added at RT under an argon atmosphere DMAP (0.75 g) and then dropwise 2,2-dimethyl-propane-1-sulfonyl chloride (0.57 ml). The reaction mixture was stirred 12 h at RT then partitioned between AcOEt and aqueous 1M HCl, the layers were separated and the aqueous layer washed with 2M aqueous KHCO3 then dried over Na2SO4. The solvent was evaporated off, the residue purified by flash chromatography (AcOEt/heptane, gradient from 0 to 40%) to give the desired 1-(2,2-dimethyl-propane-1-sulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.34 g) as a light yellow viscous oil.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].C(O)[C@H]1[O:14][C@H:13](OC2[C@H](O)[C@H](O)C(O)[C@H](O)[C@H]2O)[C@H:12]([NH3+])[C@@H](O)[C@@H]1O.P(OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.C(S)[C@@H](O)[C@H](O)CS>P([O-])([O-])([O-])=O.C(O)[C@H]1O[C@H](OC2[C@H](O)[C@H](O)C(O)[C@H](O)[C@H]2O)[C@H](NC([C@@H]([NH3+])CS)=O)[C@@H](O)[C@@H]1O>[NH:1]([C:13]([CH3:12])=[O:14])[C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4]
Reactant: [NH3+][C@H]1[C@@H](OC2[C@H](O)[C@H](O)C(O)[C@H](O)[C@H]2O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: N[C@@H](CS)C(=O)O
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: O=P([O-])([O-])[O-]
Agent: O[C@H](CS)[C@H](O)CS
Product: CC(=O)N[C@@H](CS)C(=O)O

Procedure:
Incubation of 100 μM Cys and 50 μM GlcN-Ins with 1 mM ATP in phosphate buffer, pH 7.5, containing 1 DTT after addition of cell extract supernatant resulted in an increase in Cys-GlcN-Ins from <0.2 to 26 μM over 60 min while the MSH content declined from 15 to 13 μM, corresponding to the MSH content present in the undialyzed cell extract. A parallel experiment with 100 μM AcCys in place of Cys resulted in an increase from <0.2 to 20 μM Cys-GlcN-Ins, and no change in MSH content (15 μM); however, marked conversion of AcCys to Cys had occurred by 60 min ([Cys]/[AcCys]˜3). If the MSH had increased by as much as 2 μM (10% of the change in Cys-GlcN-Ins) the change would have been detected and this experiment therefore established that conversion of Cys to Cys-GlcN-Ins is at least an order of magnitude faster than conversion of AcCys to MSH under these conditions.
Reaction SMILES: [C@@H:1]1([C:10](Cl)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[C:7](Cl)=[O:8].[F:13][C:14]([F:26])([F:25])[C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[NH2:18]>C1C=CC=CC=1>[F:13][C:14]([F:25])([F:26])[C:15]1[CH:16]=[C:17]([NH:18][C:10]([C@@H:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]2[C:7]([NH:18][C:17]2[CH:19]=[CH:20][C:21]([N+:22]([O-:24])=[O:23])=[C:15]([C:14]([F:13])([F:25])[F:26])[CH:16]=2)=[O:8])=[O:11])[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23]
Reactant: O=C(Cl)[C@@H]1CCCC[C@H]1C(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Solvent: c1ccccc1
Product: O=C(Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1)[C@@H]1CCCC[C@H]1C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1

Procedure:
Reflux a mixture of 16.73 g (0.08 moles) of trans-1,2-cyclohexane dicarboxylic acid chloride and 32.96 g (0.16 moles) of 3-trifluoromethyl-4-nitroaniline in 250 ml of benzene for 1.5 hours. Isolate the solid product of this example by filtering, washing well with hot benzene followed by ether and obtain analytically pure material by recrystallization from benzenemethanol, mp 249.5°-251° C. (dec.).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[S:9][C:10]([Cl:13])=[CH:11][CH:12]=2)[N:5]=[C:4]2[CH2:14][CH2:15][CH2:16][C:3]=12.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][CH:19]=1>>[Cl:13][C:10]1[S:9][C:8]([C:6]2[N:5]=[C:4]3[CH2:14][CH2:15][CH2:16][C:3]3=[C:2]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:23]=3)[CH:7]=2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: Clc1ccc(-c2cc(Cl)c3c(n2)CCC3)s1
Product: CCOC(=O)Cc1ccc(Nc2cc(-c3ccc(Cl)s3)nc3c2CCC3)cc1
Yield: 50.6 %

Procedure:
Following general procedure B1, 4-chloro-2-(5-chlorothiophen-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.030 g, 0.11 mmol) was reacted with ethyl 2-(4-aminophenyl)acetate (0.024 g, 0.13 mmol) to afford crude product (0.023 g) as an orange oil. MW=412.93. APCI MS m/z 413 [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=2)[N:15]=1.P(Cl)(OCC)(OCC)=O.[C:35]([NH:38][CH2:39][CH2:40][CH2:41][C:42]([O-])=[O:43])(=[O:37])[CH3:36].[Na+].C(NCCCC(O)=O)(=O)C>CN(C)C=O.O>[C:35]([NH:38][CH2:39][CH2:40][CH2:41][C:42]([O:13][CH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4](=[O:3])[N:5]1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=2)[N:15]=1)=[O:43])(=[O:37])[CH3:36]
Reactant: CC(=O)NCCCC(=O)[O-]
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Agent: CC(=O)NCCCC(=O)O
Agent: CCOP(=O)(Cl)OCC
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3OC(=O)CCCNC(C)=O)nc2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
An oily suspension (50% by weight; 0.96 g) of sodium hydride is added in the course of 15 minutes to a suspension of 3-hydroxy-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (6.15 g) in anhydrous dimethylformamide (50 cc) while the temperature is maintained in the region of 0° C., the mixture then being stirred again for 30 minutes at 0° C. Diethyl chlorophosphate (2.9 cc) is then added dropwise in the course of 30 minutes while the temperature is maintained in the region of 0° C. A solution of sodium 4-acetylaminobutanoate, prepared from 4-acetamidobutyric acid (2.9 g) in anhydrous dimethylformamide (30 cc) and an oily suspension (50% by weight; 0.96 g) of sodium hydride, is added at a temperature in the region of 0° C. to the solution obtained. The mixture is stirred for 1 hour at 0° C., then 20 hours at a temperature in the region of 20° C., and finally 4 hours at 80° C. The reaction mixture is poured into water (400 cc) and extracted with methylene chloride (3×200 cc). The organic extracts are combined and washed with water, dried and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by chromatography on silica (0.063-0.2 mm; 350 g) contained in a column 5 cm in diameter [eluant: methylene chloride/methanol (99:1 by volume)], collecting 100-cc fractions. Fractions 23 to 39 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C.; the residue is recrystallized in acetonitrile. 2-(7-Methoxy-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 4-acetylaminobutyrate (2 g), m.p. 190° C., is thereby obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]3)=[C:8]([CH3:23])[C:6]=2[N:7]=1.B(O)(O)[C:31]1[CH:36]=[N:35][CH:34]=[N:33][CH:32]=1>>[OH:21][C@@H:19]([CH3:20])[C:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:3][C:2]([C:31]4[CH:32]=[N:33][CH:34]=[N:35][CH:36]=4)=[N:7][C:6]=3[C:8]=2[CH3:23])[CH2:13][CH2:14]1)=[O:22]
Reactant: OB(O)c1cncnc1
Reactant: Cc1c(CN2CCN(C(=O)[C@H](C)O)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Product: Cc1c(CN2CCN(C(=O)[C@H](C)O)CC2)sc2c(N3CCOCC3)nc(-c3cncnc3)nc12
Yield: 69.3 %

Procedure:
(S)-1-(4-((2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (60 mg) was reacted with 28 mg of pyrimidin-5-yl-5-boronic acid via General Procedure A to give 45.7 mg of 205. MS (Q1) 484.3 (M)+.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[Na].Cl[CH2:17]/[CH:18]=[CH:19]/[CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31]>CN(C)C=O>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:17]/[CH:18]=[CH:19]/[CH2:20][N:21]3[C:29](=[O:30])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]3=[O:31])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1c2ccccc2C(=O)N1C/C=C/CCl
Reactant: Oc1ccc(-n2ccnc2)cc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C/C=C/COc1ccc(-n2ccnc2)cc1

Procedure:
A solution of 16.0 g of 4-(1H-imidazol-1-yl)phenol in 250 ml of dimethylformamide, is treated with 4.2 g of 60% NaH. To the suspension of the sodium salt, 23.5 g of (E)-2-[4-chloro-2-buten-1-yl)-1H-isoindole-1,3(2H)-dione is added, and the reaction mixture stirred and heated on the steam bath for 16 hours. The dimethylformamide is removed in vacuo, and the residue stirred with 250 ml of water. The insolubles are collected, washed with water, and dried. Recrystallization from ethanol gives the desired product as a solid, m.p. 170°-171° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][O:11][CH3:12].[CH2:20]([Li])CCC.CI.O>O1CCCC1>[CH3:1][O:2][C:3]1[C:4]([CH3:20])=[C:5]([NH:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:18])[CH3:17])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][O:11][CH3:12]
Reactant: [Li]CCCC
Reactant: COCOc1ccc(NC(=O)C(C)(C)C)cc1OC
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: COCOc1ccc(NC(=O)C(C)(C)C)c(C)c1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
To a solution of N-[3-methoxy-4-(methoxymethoxy)phenyl]-2,2-dimethylpropanamide (500 mg, 1.87 mmol) in tetrahydrofuran (10 ml) was added dropwise 1.59M-n-butyllithium (2.94 ml, 4.68 mmol) at −15° C., and the resulting mixture was slowly warmed up to 0° C. After 2 hours, a solution of methyl iodide (0.175 ml, 2.81 mmol) in tetrahydrofuran (0.5 ml) was added dropwise thereto. After 1 hour, the resulting mixture was warmed up to room temperature. After 14 hours, the reaction solution was poured into water (50 ml) and extracted with ethyl acetate (30 ml×3), and the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain N-[3-methoxy-4-(methoxymethoxy)-2-methylphenyl]-2,2-dimethylpropanamide (424 mg, 81%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1/[CH:10]=[CH:11]/[C:12]([OH:14])=O)([O-:3])=[O:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:37][CH2:38][C:39]1[N:43]([C:44]2[S:45][C:46]([CH2:58][CH3:59])=[CH:47][C:48]=2[C:49](=[O:57])[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[Cl:56])[C:42]([CH3:60])=[N:41][N:40]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(N(CC)CC)C>[Cl:56][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=1[C:49]([C:48]1[CH:47]=[C:46]([CH2:58][CH3:59])[S:45][C:44]=1[N:43]1[C:42]([CH3:60])=[N:41][N:40]=[C:39]1[CH2:38][NH:37][C:12](=[O:14])/[CH:11]=[CH:10]/[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])=[O:57]
Reactant: O=C(O)/C=C/c1ccccc1[N+](=O)[O-]
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)/C=C/c2ccccc2[N+](=O)[O-])s1
Yield: 68.2 %

Procedure:
Reaction was carried out in the same manner as in Example 186 using trans-3-(2-nitrophenyl)propenoic acid (1.93 g), 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazole di-p-toluenesulfonate (7.42 g), triethylamine (5.6 ml) and 1-benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate (Bop reagent, 4.42 g), and the obtained crude crystals were recrystallized from ethyl acetate to give 3.65 g of trans-N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)-3-(2-nitrophenyl)propenamide.
Reaction SMILES: [H-].[Na+].C(OC(=O)[NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[NH:16][S:17]([CH2:20][CH2:21][CH2:22][CH2:23]Cl)(=[O:19])=[O:18])(C)(C)C.[I-].[Na+]>>[O:18]=[S:17]1(=[O:19])[CH2:20][CH2:21][CH2:22][CH2:23][N:16]1[C@@H:11]1[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]1[NH2:9]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1NS(=O)(=O)CCCCCl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Product: N[C@@H]1CCCC[C@H]1N1CCCCS1(=O)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 15 mg, 0.38 mmol) was added at 0° C. to a solution of trans-[2-(4-chloro-butane-1-sulfonylamino)-cyclohexyl]-carbamic acid tert-butyl ester (125 mg, 0.34 mmol) and sodium iodide (51 mg, 0.34 mmol), and the reaction mixture was stirred at room temperature for 24 h, then another portion of sodium hydride (15 mg, 0.38 mmol) was added, and the reaction mixture was heated at 60° C. for 3 h. After cooling, the solution was partitioned between heptane/ethyl acetate (1:1) and water. The organic layer was washed with brine, evaporated, and chromatographed (SiO2, heptane-ethyl acetate gradient). The title compound was obtained from this material in accordance with the general method of example 27b. Off-white solid, MS (ISP) 233.1 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH2:16][C:17]([NH2:19])=O)=[C:9]3[N:14]([CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(OCC)C>[C:1]1([C:7]2[C:8]([CH2:16][CH2:17][NH2:19])=[C:9]3[N:14]([CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)Cc1c(-c2ccccc2)cn2ccccc12
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: NCCc1c(-c2ccccc2)cn2ccccc12
Temperature: 25 °C
Yield: 53 %

Procedure:
2-Pyridinepropaneamide (8.0 g, 53 mmol) was dissolved in warm acetone (500 mL). 2-Bromoacetophenone (12.0 g, 60 mmol) was added and the reaction mixture was heated under reflux overnight. After standing at room temperature for 2 days, the solvent was decanted from the tan precipitate, which was dissolved in ethanol and heated under reflux for 6 h. After standing overnight at ambient temperature, the ethanol was removed under reduced pressure to give a residue which was recrystallized from heptane (500 mL) to give 2-(2-phenyl-indolizin-1-yl)acetamide. 2-(2-Phenylindolizin-1-yl)acetamide (450 mg, 1.8 mmol) was suspended in ethyl ether. To the suspension was added lithium aluminum hydride (360 mg) and the reaction mixture was heated under reflux overnight under a nitrogen atmosphere. After cooling to room temperature, an aqueous solution of Rochelle salt was cautiously added with stirring until a solution was observed. The phases were separated and the aqueous phase was extracted 3 times with ether. The combined organic layers were extracted with 0.1 N HCl, and the aqueous layer was made basic with 2.5 N NaOH. The aqueous phase was extracted with methylene chloride three times and the organic phase was evaporated under reduced pressure to give crude product. The product was purified by chromatography on silica gel eluting with 5-11% methanol in methylene chloride containing 1% ammonium hydroxide. A 53% yield of the title compound was obtained, mp 212-214° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH2:12][OH:13])=[CH:5]2.N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH2:12][O:13][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH:5]2
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cn1c(CO)cc2cc(Br)ccc21
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: Cn1c(CO[Si](C)(C)C(C)(C)C)cc2cc(Br)ccc21
Reaction time: 1 h
Yield: 96.5 %

Procedure:
To a solution of (5-bromo-1-methyl-1H-indol-2-yl)methanol (7.8 g, ca. 31.3 mmol) in CH2Cl2 (80 mL) was added imidazole (2.6 g, 38.2 mmol, 1.2 eq) followed by TBS-Cl (5.2 g, 34.5 mmol, 1.1 eq) at 0° C. The reaction was monitored by LC-MS. After 1 h, the reaction was quenched with water then extracted by CH2Cl2 (3×50 mL). The solvent was concentrated to give a crude product which was purified by flash column chromatography (50% CH2Cl2 in hexanes) to afford the title compound (10.7 g, 30.2 mmol, 96%) over three steps as an off-white solid.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]2[C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]=1[CH3:30].Cl.[CH3:32][NH:33][OH:34]>CN(C=O)C>[CH3:30][C:15]1[C:14]([CH3:13])=[CH:19][CH:18]=[CH:17][C:16]=1[NH:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=1[C:27]([N:33]([OH:34])[CH3:32])=[O:28]
Reactant: Cc1cccc(Nc2ccccc2C(=O)O)c1C
Reactant: CNO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1cccc(Nc2ccccc2C(=O)N(C)O)c1C
Temperature: 24 °C
Reaction time: 20 h

Procedure:
1,1'-Carbonyl-diimidazole (5.35 g; 0.033 mol) is added to a solution of mefanamic acid (7.2% g; 0.03 mol) in dry DMF (100 ml). The solution is stirred at 24° C. for 20 hours and then briefly warmed to 50° C. N-Methylhydroxylamine hydrochloride (2.7 g; 0.032 mo) is added to the cooled solution at 24° C. and stirred for two days. The reaction mixture is then evaporated to dryness and the residue is taken up in CH2Cl2, washed with water, and dried over sodium sulfate and evaporated. The residue is flash chromatographed through silica gel and eluted with n-hexane-CH2Cl2 -EtOAc (2:1:1) yielding a crude product which is rechromatographed through silica gel and eluted with n-hexane-CH2Cl2 -EtOAc (4:5:1). The product is recrystallized from n-pentane to give white crystals. Yield 1.5 g (18.5%); mp 70°-71° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[NH:11][C:12](=[O:19])[C:13](=[CH:17][CH:18]=2)[C:14](O)=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].S(Cl)([Cl:22])=O>>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[NH:11][C:12](=[O:19])[C:13](=[CH:17][CH:18]=2)[CH2:14][Cl:22])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(-c2cccc([N+](=O)[O-])c2)[nH]c1=O
Product: O=c1[nH]c(-c2cccc([N+](=O)[O-])c2)ccc1CCl

Procedure:
A 5 g. sample of 6-(m-nitrophenyl)-1,2-dihydro-2-oxonicotinic acid is suspended in 100 ml. thionyl chloride and stirred at room temperature overnight. The product 6-(m-nitrophenyl)-1,2-dihydro-2-oxonicotinyl chloride is carefully filtered off and washed with hexane and used directly in the preparation of compounds of the present invention.
Reaction SMILES: O[CH2:2][C:3]1[N:7]([CH3:8])[C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[O:18]=[C:16]1[C:15]2[C:14](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13](=[O:23])[N:17]1[CH2:2][C:3]1[N:7]([CH3:8])[C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COC(=O)c1ccc(CO)n1C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
590 mg of methyl 5-(hydroxymethyl)-1-methyl-1H-pyrrole-2-carboxylate, 770 mg of phthalimide, and 1.83 g of triphenylphosphine were dissolved in 10.0 mL of THF, and 2.75 mL of diethyl azodicarboxylate was added thereto under ice-cooling, followed by stirring at room temperature overnight. The reaction liquid was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1 to 1:1) to obtain 650 mg of methyl 5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-methyl-1H-pyrrole-2-carboxylate.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:11]=3)([CH3:4])([CH3:3])[CH3:2].CCCCCC.C([Li])CCC.[C:33]1([C:39]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[C:40]2[CH:44]=[CH:43][CH:42]=[CH:41]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1.O>[CH:40]1([C:39]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:11]2[C:10]3[CH2:9][C:8]4[C:16](=[CH:17][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=4)[C:15]=3[CH:14]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=2)[CH:41]=[CH:42][CH:43]=[CH:44]1
Reactant: C1=CC(=C(c2ccccc2)c2ccccc2)C=C1
Reactant: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)ccc1C2
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)cc(C(c3ccccc3)(c3ccccc3)C3C=CC=C3)c1C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2.5 g (9.0 mmol) of 3,6-di-tert-butylfluorene in 40 ml of THF, 6.1 ml (9.8 mmol) of a hexane solution of n-butyllithium was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for 4 hours. The resulting solution was ice cooled again, and thereto was dropwise added a solution of 2.5 g (10.8 mmol) of 6,6-diphenylfulvene in 30 ml of THF in a nitrogen atmosphere, followed by stirring at room temperature for 5 hours. Then, 50 ml of water was added. The organic phase extracted with diethyl ether and separated was dried over magnesium sulfate and then filtered. From the filtrate, the solvent was removed under reduced pressure to obtain a solid. The solid was recrystallized from methanol to obtain 3.4 g of a slightly yellow solid. The analyzed values are given below.