Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-]#N.[Na+].Br[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[C:7]([F:15])[CH:6]=1.C1(C)C=CC=CC=1.[CH3:23][NH:24]CCNC>N.[Cu]I>[C:23]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[C:7]([F:15])[CH:6]=1)#[N:24]
Reactant: CNCCNC
Reactant: CC(=O)Nc1ccc(Br)cc1F
Agent: [Cu]I
Agent: N
Agent: [C-]#N
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc(C#N)cc1F
Temperature: 110 °C
Reaction time: 24 h
Yield: 81.2 %

Procedure:
A Schlenk tube was charged with NaCN (137 mg, 2.80 mmol), CuI (44 mg, 0.23 mmol, 10 mol %), KI (77 mg, 0.46 mmol, 20 mol %), and N-(4-bromo-2-fluorophenyl)acetamide (540 mg, 2.33 mmol), briefly evacuated and backfilled with argon three times. Anhydrous toluene (1.2 mL) and N,N′-dimethylethylenediamine (250 μL, 2.35 mmol) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 110° C. for 24 h. The resulting suspension was allowed to reach room temperature, diluted with 30% aq ammonia (2 mL), and extracted with ethyl acetate (4×2 mL). The combined organic phases were dried over MgSO4, concentrated, and the residue was purified by flash chromatography on silica gel (hexane/ethyl acetate 1:1) to provide the desired product as a fine white powder (337 mg, 87% yield). Mp 169.5-171.5° C.; 1H NMR (400 MHz, CDCl3, J values are reported in Hz): δ 8.59 (t, J=8.4, 1H), 7.63 (bs, 1H), 7.48 (d, J=8.4, 1H), 7.41 (dd, J=10.6, J=1.8, 1H), 2.30 (s, 3H); 13C NMR (100 MHz, CDCl3): 169.0, 151.3 (d, J=244 Hz), 131.6 (d, J=9.6 Hz), 129.9 (d, J=3.5 Hz), 121.9, 118.7 (d, J=22.8 Hz), 118.1 (d, J=2.9 Hz), 107.1 (d, J=9.3 Hz), 25.3; IR (neat, cm−1): 3317, 2235, 1699, 1593, 1515, 834, 707. Anal. Calcd. for C9H7FN2O: C, 60.67; H, 3.96; N, 15.72. Found: C, 60.42; H, 3.94; N, 15.63.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([N+:13]([O-])=O)[CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1>C(O)C.C(OCC)(=O)C.[Pd]>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=2)[NH2:13])[CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1cccc(N2CCOCC2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cccc(N2CCOCC2)c1

Procedure:
Meta-morpholino nitrobenzene (2a) (2 g, 9.6 mmol) is hydrogenated in a mixture of ethanol and ethyl acetate (50 ml/10 ml), over 10% Pd on carbon (200 mg) for 1 hour. The catalyst is removed by filtration and the solvent removed by evaporation to yield a solid, which is dried under vacuum; ES+ (M+1) 179.35; mp 125.4-127.6° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]2)[C:5]([N+:16]([O-:18])=[O:17])=[CH:4][N:3]=1.[N:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[NH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:19]1([C:2]2[N:7]=[C:6]([NH:8][C@H:9]3[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]3)[C:5]([N+:16]([O-:18])=[O:17])=[CH:4][N:3]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[CH:20]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1N[C@H]1CC[C@H](O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cnc(-n2cnc3ccccc32)nc1N[C@H]1CC[C@H](O)CC1

Procedure:
A mixture of trans-4-(2-chloro-5nitropyrimidin-4-ylamino)cyclohexanol (310 mg), benzimidazole (390 mg), and potassium carbonate (0.5 g) was heated in acetonitrile at 60° C. for 2 hours. The mixture was concentrated onto silicon gel and purified by column chromatography (DCM:EtOAc:MeOH 70:22:8) to give 350 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:23])[NH:8][CH2:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])=[C:5]([C:24]([OH:26])=O)[CH:4]=[N:3]1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:16][C:15]1[O:14][C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:12][C:11]=1[CH2:10][CH2:9][NH:8][C:7]([C:6]1[N:2]([CH3:1])[N:3]=[CH:4][C:5]=1[C:24]([N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26])=[O:23]
Reactant: Cc1oc(-c2ccccc2)nc1CCNC(=O)c1c(C(=O)O)cnn1C
Reactant: C1CCNC1
Product: Cc1oc(-c2ccccc2)nc1CCNC(=O)c1c(C(=O)N2CCCC2)cnn1C

Procedure:
The product was obtained starting from 1-methyl-5-(2-(5-methyl-2-phenyloxazol-4-yl)ethylcarbamoyl)-1H-pyrazole-4-carboxylic acid (40 mg, 113 μmol) and pyrrolidine (8.03 mg, 9.34 μL, 113 μmol) according to the method described in example 37, step 3 as off-white solid (22.1 mg, 54.2 μmol, 48.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1>C(O)C.[Pt]=O>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]([C:5]2[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1
Agent: O=[Pt]
Solvent: CCO
Product: Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Yield: 79.2 %

Procedure:
A suspension of 14.4g (54.8 mmol) of 4-chloro-4'-nitrobenzophenone and 66.9 mg, (0.5 mole %) of platinum oxide was stirred under hydrogen in 300 ml of ethanol for 2 hours The mixture was filtered, evaporated and purified by flash column chromatography (2-8% EtOAc/CH2C12) to obtain 10.05 g (72%) of the desired product as a yellow solid. 1H nmr (CDCl3) δ4.16 (2H, br s), 6.67 (2H, d), 7.43 (2H, d), 7.68 (2H, d), 7.69 (2H, d).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:36]([C:38]1[C:39]([N:47]2[CH2:52][CH2:51][CH:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]2)=[CH:40][C:41]([O:45][CH3:46])=[C:42]([CH:44]=1)[NH2:43])[CH3:37].Cl.O1CCOCC1.N>CO>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:43][C:42]3[CH:44]=[C:38]([CH2:36][CH3:37])[C:39]([N:47]4[CH2:48][CH2:49][CH:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:51][CH2:52]4)=[CH:40][C:41]=3[O:45][CH3:46])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: CCc1cc(N)c(OC)cc1N1CCC(CCS(C)(=O)=O)CC1
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: CO
Product: CCc1cc(Nc2nccc(-c3c(-c4ccc(OC)c(C(=O)Nc5c(F)cccc5F)c4)nc4ccccn34)n2)c(OC)cc1N1CCC(CCS(C)(=O)=O)CC1
Temperature: 180 °C
Yield: 56.2 %

Procedure:
In a microwave vial with septum cap, 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (0.131 g, 0.267 mmol) and 5-ethyl-2-(methyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperidinyl}aniline (0.091 g, 0.27 mmol) were taken up in 1,1,1-trifluoroethanol (1.5 mL) and 4M HCl in dioxane (0.134 mL, 0.535 mmol) was added. The vial was sealed and heated in the microwave at 180° C. for 40 min. Reaction was complete by MS, it was cooled to rt, neutralized with 7N ammonia in MeOH, and concentrated in vacuo onto silica gel and flash chromatographed. The desired fractions were combined and concentrated and the resulting solid was triturated with diethyl ether, filtered and air dried to give the title compound (0.12 g, 0.15 mmol, 56%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.75 (s, 1H), 9.23-9.40 (m, 1H), 8.44 (s, 1H), 8.21 (d, J=5.2 Hz, 1H), 8.08 (s, 1H), 7.75 (dd, J=8.4, 1.6 Hz, 1H), 7.67 (d, J=9.0 Hz, 1H), 7.49 (s, 1H), 7.29-7.45 (m, 2H), 7.21-7.29 (m, 1H), 7.07-7.21 (m, 2H), 6.91 (t, J=6.8 Hz, 1H), 6.78 (s, 1H), 6.54 (d, J=5.1 Hz, 1H), 3.95 (s, 3H), 3.76 (s, 3H), 3.06-3.20 (m, 2H), 2.86-3.01 (m, 5H), 2.57-2.72 (m, 2H), 2.51 (q, J=7.5 Hz, 2H), 1.75 (dd, J=11.6, 0.6 Hz, 2H), 1.60-1.71 (m, 2H), 1.40-1.55 (m, 1H), 1.20-1.39 (m, 2H), 1.06 (t, J=7.5 Hz, 3H). MS (M+H, ES+) 796.
Reaction SMILES: II.Br[C:4]1[CH:9]=[CH:8][C:7](Cl)=[C:6](OCC)[CH:5]=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[C:14]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOc1cc(Br)ccc1Cl
Agent: II
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
8.7 g (357.06 mmol) of Mg and a small amount of iodine were dissolved in 200 ml of THF, and 84.6 g (324.6 mmol) of 1-bromo-4-chloro-3-ethoxybenzene dissolved in 500 ml of THF was added dropwise to the resulting solution. After addition, the resulting mixture was refluxed for 3 hours to prepare a Grignard reagent which was then cooled to room temperature. Thereafter, a Grignard reagent containing 50.2 g (357.06 mmol) of benzoyl chloride was added dropwise to the obtained product and stirred for 5 hours. After a reaction, the reaction solution was washed with water, the solvent was removed, and the obtained product was purified by column chromatography to obtain a benzophenone derivative represented by the following formula (42) as 29.6 g (113.6 mmol, yield of 35%) of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-])=[O:20])[CH:17]=[CH:18][C:13]=2[N:12]([CH2:22][O:23][CH3:24])[C:11](=[O:25])[CH2:10][N:9]=1.O1CCCC1.O.O.O.C([O-])(=O)C.[Na+].N>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([NH:19][OH:20])[CH:17]=[CH:18][C:13]=2[N:12]([CH2:22][O:23][CH3:24])[C:11](=[O:25])[CH2:10][N:9]=1
Reactant: COCN1C(=O)CN=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc21
Agent: CC(=O)[O-]
Agent: N
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COCN1C(=O)CN=C(c2ccccc2Cl)c2cc(NO)ccc21

Procedure:
A mixture of 3.6 g. (0.01 mol) of 5-(2-chlorophenyl)-1,3-dihydro-1-methoxymethyl-7-nitro-2H-1,4-benzodiazepin-2-one, 100 ml. of tetrahydrofuran, 50 ml. of methanol, 13.6 g. of sodium acetate trihydrate and 11.25 g. of stannous chloride dihydrate was stirred under nitrogen for 5 hours. 500 ml. of methylene chloride and 10 ml. of concentrated ammonia was added. The inorganic material was separated by filtration. The filtrate was washed with 1N sodium hydroxide solution, dried over sodium sulfate and evaporated. Crystallization of the residue from methylene chloride/ether gave light yellow product with m.p. 205°-208° dec. For analysis it was recrystallized from 2 -propanol/tetrahydrofuran.
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:6]2[C:29]([CH:30]3[CH2:32][CH2:31]3)=[CH:28][C:9]([CH2:10][N:11]3[CH2:16][CH2:15][CH:14]([N:17]4[CH:22]=[CH:21][C:20]([C:23]([O:25]C)=[O:24])=[CH:19][C:18]4=[O:27])[CH2:13][CH2:12]3)=[C:8]([O:33][CH:34]([CH3:36])[CH3:35])[CH:7]=2)[CH2:5][CH2:4]1>C(O)C>[CH:3]1([C:6]2[C:29]([CH:30]3[CH2:31][CH2:32]3)=[CH:28][C:9]([CH2:10][N:11]3[CH2:16][CH2:15][CH:14]([N:17]4[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][C:18]4=[O:27])[CH2:13][CH2:12]3)=[C:8]([O:33][CH:34]([CH3:36])[CH3:35])[CH:7]=2)[CH2:4][CH2:5]1
Reactant: COC(=O)c1ccn(C2CCN(Cc3cc(C4CC4)c(C4CC4)cc3OC(C)C)CC2)c(=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1cc(C2CC2)c(C2CC2)cc1CN1CCC(n2ccc(C(=O)O)cc2=O)CC1
Reaction time: 2 h
Yield: 69.2 %

Procedure:
A 2 M aqueous sodium hydroxide solution (3 mL) was added to an ethanol (8 mL) solution of methyl 1-(1-(4,5-dicyclopropyl-2-isopropoxybenzyl)piperidin-4-yl)-2-oxo-1,2-dihydropyridine-4-carboxylate (426 mg), and the mixture was stirred at 90 C for 2 hours in a nitrogen atmosphere. The solvent in the reaction mixture was distilled off under reduced pressure. The obtained residue was dissolved in water, and the solution was neutralized with 2 M hydrochloric acid. The resulting solid was collected by filtration and dissolved in ethyl acetate and THF. The solvent in the obtained solution was distilled off under reduced pressure. The obtained residue was crystallized (ethyl acetate/hexane) and recrystallized (ethanol/hexane) to obtain the title compound (286 mg).
Reaction SMILES: Br[C:2]1[C:3]([O:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].[B-](F)(F)(F)[C:23]1[O:27][CH:26]=[CH:25][CH:24]=1.[K+].C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC.Cl>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH:12]1([O:11][C:3]2[C:2]([C:26]3[O:27][CH:23]=[CH:24][CH:25]=3)=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: F[B-](F)(F)c1ccco1
Reactant: O=C(O)c1cnc(OC2CCC2)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)c1cnc(OC2CCC2)c(-c2ccco2)c1
Temperature: 120 °C
Yield: 74.7 %

Procedure:
In a 50 mL 4-necked flask, 5-bromo-6-cyclobutoxynicotinic acid (1 g, 3.68 mmol, Eq: 1.00, preparation see Example 47) and cesium carbonate (3.59 g, 11.0 mmol, Eq: 3) were combined with toluene (25 mL) and water (2.8 mL) to give a colorless solution. The reaction mixture was 3× degassed and purged with argon before successively potassium 2-furantrifluoroborate (959 mg, 5.51 mmol, Eq: 1.5), palladium(II) acetate (41.3 mg, 184 μmol, Eq: 0.05) and butyldi-1-adamantylphosphine (198 mg, 551 μmol, Eq: 0.15) were added. The evacuating-purging cycle was repeated after each addition. The reaction mixture was then heated to 120° C. for 5 hours when TLC showed that the starting material had disappeared. Work up: The reaction mixture was cooled to RT, poured into 30 mL 1N HCl and extracted with AcOEt/THF 2:1 (4×50 mL). The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude material was then purified by triturating it with methanol to afford 713 mg of the title compound as yellow solid; MS (EI) 258.4 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[CH2:6][CH2:7][PH:8](=[O:10])[OH:9].Br[CH2:18][CH2:19][O:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[CH2:6][CH2:7][PH:8](=[O:9])[O:10][CH2:18][CH2:19][O:20][CH3:21]
Reactant: COCCBr
Reactant: COc1cc(CC[PH](=O)O)ccc1[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COCCO[PH](=O)CCc1ccc([N+](=O)[O-])c(OC)c1
Temperature: 50 °C
Yield: 45 %

Procedure:
A mixture of (3-methoxy-4-nitrobenzyl)methylphosphinic acid (Compound 216C, 0.250 g, 1.02 mmol) and 1-bromo-2-methoxy ethane (0.287 mL, 3.06 mmol) in DMF (3.0 mL) was charged with potassium carbonate (0.169 g, 1.22 mmol) and n-Bu4NI (0.188 g, 0.510 mmol). The reaction mixture was allowed to heat at 50° C. for 16 hours with stirring. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (15 mL). The organic layer was washed with water (10 mL), washed with brine (10 mL), dried over Na2SO4, filtered, concentrated under reduced pressure to yield a yellow oil. The crude material was purified by silica gel chromatography on the combi-flash Rf system using 1:1 EtOAc-DCM/MeOH (100:0→90:10) as eluent. The fractions containing product were combined and concentrated under reduced pressure to yield a yellow oil, 0.140 g (45% yield). 1H NMR (CDCl3, 400 MHz): δ=1.47 (d, J=13.89 Hz, 3 H), 3.24 (dd, J=17.43, 3.79 Hz, 2 H), 3.39 (s, 3 H), 3.51-3.62 (m, 2 H), 3.98 (s, 3 H), 4.14 (ddd, J=8.27, 4.42, 4.23 Hz, 2 H), 6.93 (dt, J=8.34, 1.89 Hz, 1 H), 7.12 (t, J=1.77 Hz, 1 H), 7.85 (dd, J=8.21, 0.63 Hz, 1 H). MS (ES+): m/z 304.08 [MH+] (TOF, polar).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:3])[CH3:2].[N+:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O)([O-:16])=[O:15].CC(O)=O.N1CCCCC1>C1C=CC=CC=1.CCOCC.CCCCCC>[C:1]([O:4][CH2:5][C:6](=[O:13])[C:7](=[CH:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([N+:14]([O-:16])=[O:15])[CH:18]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CC(=O)COC(C)=O
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CC(=O)O
Product: CCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)COC(C)=O
Reaction time: 0.5 h

Procedure:
A solution of ethyl 4-acetoxyacetoacetate (23.0 g, 0.122 mole, Tet., 28, 967 (1972)) and 3-nitrobenzaldehyde (18.47 g, 0.122 mole) in 125 ml of benzene was treated with HOAc (0.6 ml) and piperidine (0.6 ml) and heated at reflux temperature. Collection of water ceased after 0.5 hour; therefore, additional HOAc (1 ml) and piperidine (1 ml) were added and refluxing continued. A total of 2.0 ml water was collected. The cooled mixture was washed with water (2x) and saturated brine, dried over anhydrous magnesium sulfate, treated with Darco to remove color and concentrated in vacuo to give an oil that solidified on standing. Trituration with IPE/Et2O/Hexane and stirring overnight to pulverize the solids afforded 24.2 g of the title
Reaction SMILES: C(OC([N:8]1[CH:17]([CH3:18])[CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:19]([CH3:21])[CH3:20])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.FC1C=CC(C2N(C(C)C)N=C3C=2CC(C)NCC3)=CC=1>>[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:12]2[N:13]([CH:19]([CH3:20])[CH3:21])[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH:17]([CH3:18])[CH2:16]3)=[CH:33][CH:32]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC1Cc2nn(C(C)C)c(OS(=O)(=O)C(F)(F)F)c2CCN1C(=O)OC(C)(C)C
Agent: CC1Cc2c(nn(C(C)C)c2-c2ccc(F)cc2)CCN1
Product: CC1Cc2nn(C(C)C)c(-c3ccc(F)cc3)c2CCN1

Procedure:
The title compound (127 mg) was prepared as in Example 311 using 260 mg of 2-isopropyl-7-methyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester and 115 of 4-fluorophenylboronic acid. The reaction sequence also yielded 3-(4-fluoro-phenyl)-2-isopropyl-5-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene. MS (ESI): exact mass calculated for C17H22FN3, 287.18; found, m/z 288.5 [M+H]+. 1H NMR (600 MHz, CD3OD): 7.39-7.37 (m, 2H), 7.32-7.28 (m, 2H), 4.36 (m, 1H), 3.61-3.56 (m, 1H), 3.50-3.47 (m, 1H), 3.20-3.08 (m, 3H), 2.85-2.80 (m, 1H), 2.73-2.69 (m, 1H), 1.46 (d, J=6.6 Hz, 3H), 1.41-1.38 (m, 6H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].[CH3:18][O:19][C:20](=[O:45])[N:21]=[C:22]([S:43][CH3:44])[C:23](=[N:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=1)[C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([OH:32])[C:25]=1[F:33].O>CN(C=O)C.C(OCC)(=O)C>[CH3:18][O:19][C:20](=[O:45])[N:21]=[C:22]([S:43][CH3:44])[C:23]([C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH2:8][CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[C:25]=1[F:33])=[N:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(C#N)cc1)c1cc(OC)cc(O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)N=C(SC)C(=Nc1ccc(C#N)cc1)c1cc(OC)cc(OCCO[Si](C)(C)C(C)(C)C)c1F
Temperature: 50 °C
Reaction time: 5 h
Yield: 77.5 %

Procedure:
After adding 1.8 g of potassium carbonate and 3 g of (2-bromoethoxy)-t-butyldimethylsilane to a solution of 3.45 g of [2-(4-cyanophenylimino)-2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-1-methylsulfanylethylidene]carbamic acid methyl ester (Example (163b)) in 10 ml of DMF, the mixture was stirred at 50° C. for 5 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate) to give the title compound (3.73 g, isomeric mixture) as a light yellow solid.
Reaction SMILES: [C:1]1([C:13]2[C:14](=[O:34])[NH:15][C:16](=[O:33])[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:25]=3)[NH:20][CH:19]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1>CO>[C:1]1([C@H:13]2[C@H:17]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:25]=4)[NH:20][CH:19]=3)[C:16](=[O:33])[NH:15][C:14]2=[O:34])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2ccc(-c3ccccc3)cc12
Solvent: CO
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1c[nH]c2ccc(-c3ccccc3)cc12

Procedure:
3-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-(5-phenyl-1H-indol-3-yl)pyrrole-2,5-dione, prepared as in Example 32, was reduced with Mg in methanol as described in Example 2, Procedure C, to yield (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-(5-phenyl-1H-indol-3-yl)pyrrolidine-2,5-dione. 1H NMR (CD3OD) δ: 2.00-2.16 (m, 2H), 2.94 (t, J=6.0 Hz, 2H), 3.92-3.99 (m, 1H), 4.00-4.08 (m, 1H), 4.36 (d, J=6.4 Hz, 1H), 4.68 (d, J=6.4 Hz 1H), 6.88-6.97 (m, 2H), 7.04 (s, 1H), 7.12-7.15 (m, 1H), 7.17-7.47 (m, 9H).
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:8]=[C:9]([O:17][CH3:18])[C:10]([OH:16])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].[C:19](OCC)(=O)C.CCCCCC>CO>[CH3:19][O:13][C:12](=[O:14])[C:11]1[CH:15]=[C:7]([Br:6])[CH:8]=[C:9]([O:17][CH3:18])[C:10]=1[OH:16]
Reactant: CCOC(C)=O
Reactant: COc1cc(Br)cc(C(=O)O)c1O
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)c1cc(Br)cc(OC)c1O

Procedure:
To prepare this compound, initially 1.0 mL of 98% concentrated sulfuric acid was added to a solution of 5-bromo-2-hydroxy-3-methoxy-benzoic acid, (compound 6) (1.0 g, 4.0 mmol) in 50 ml of methanol. The reaction mixture was refluxed overnight until thin layer chromatography using 20% ethyl acetate and 80% hexane as the mobile phase indicated that the reaction was complete. After evaporating the methanol, the residue was dissolved in 60 mL of ethyl acetate and washed with a saturated NaHCO3 aqueous solution and then brine. After drying with anhydrous sodium sulfate, the solution was concentrated, and the crude product was purified on a silica gel column to isolate the intermediate, 5-bromo-2-hydroxy-3-methoxy-benzoic acid methyl ester. The yield of this intermediate was 94%. The 1H-NMR spectrum (300 MHz, CDCl3) of the purified product was: 3.88 (s 3H), 3.95 (s, 3H), 7.09 (d, 1H), 7.55 (t, 1H), 10.96 (d, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CC(N(C)C)=O>[I:8][C:5]1[CH:6]=[CH:7][C:2]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:3][CH:4]=1
Reactant: Clc1ccc(I)cn1
Reactant: C1CNCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Ic1ccc(N2CCNCC2)nc1
Temperature: 120 °C
Yield: 82 %

Procedure:
To a stirred solution of 2-chloro-5-iodo-pyridine (CAS number 69045-79-0, 10.52 g, 43.9 mmol) and diisopropylethylamine (11.5 mL, 65.9 mmol) in DMA (200 mL) was added piperazine (15.14 g, 0.176 mol). The mixture was then heated to 120° C. for 20 hours. The solid precipitate was then filtered off, and the filtrate evaporated in vacuo. The residue was partitioned between EtOAc (100 mL) and water (100 mL) and the layers were separated. The aqueous layer was then extracted with EtOAc (2×100 mL). The combined organic extracts were then dried, (MgSO4), filtered and concentrated in vacuo, to give 1-(5-iodopyridin-2-yl)piperazine as a yellow solid (10.42 g, 36 mmol, 82%).