Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[C@@H:19]([NH2:21])[CH3:20])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1.CCN(C(C)C)C(C)C>CC(O)C>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[C@@H:19]([NH:21][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][N:27]3[CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH3:20])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1cc(F)cc(F)c1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)cc2n1-c1cc(F)cc(F)c1
Temperature: 90 °C
Yield: 40.2 %

Procedure:
A mixture of (S)-1-[1-(3,5-difluorophenyl)-6-fluoro-1H-benzoimidazol-2-yl]ethylamine (206 mg, 0.71 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (169 mg, 0.71 mmol) and DIPEA (0.37 mL, 2.1 mmol) in IPA (1.4 mL) was heated in a sealed tube for 20 h at 90° C. After cooling to RT, the volatiles were removed in vacuo and the resulting residue purified by column chromatography (Si—PPC, gradient 0-10% 2M NH3 in MeOH/DCM) to afford the title compound as a colourless glass (141 mg, 40%). LCMS (Method C): RT 3.38 min [M+H]+ 494. 1H NMR (CDCl3, 400 MHz): δ 8.29-8.28 (1H, m), 7.97-7.96 (1H, m), 7.72-7.68 (1H, m), 7.10-7.01 (3H, m), 6.97-6.91 (1H, m), 6.86-6.82 (1H, m), 6.37 (1H, bs), 5.79-5.67 (2H, m), 4.18-4.13 (1H, m), 3.80-3.73 (1H, m), 2.11-1.97 (3H, m), 1.80-1.63 (6H, m).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH3:6][C:7]1[N+:8]([O-])=[C:9]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[O:10][C:11]=1[CH3:12]>C(Cl)Cl>[Cl:3][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[O:10][C:11]=1[CH3:12]
Reactant: COC(=O)c1ccc(-c2oc(C)c(C)[n+]2[O-])cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Temperature: 40 °C
Reaction time: 16 h
Yield: 76.8 %

Procedure:
POCl3 (2.23 mL, 24.3 mmol) was added dropwise to a stirred solution of N-oxide 1 (5.0 g, 20.2 mmol) in dry DCM (100 mL) and the mixture stirred at 40° C. for 16 h. The solution was poured into a slurry of ice/1 M NaOH solution (100 mL) and the mixture stirred for 10 min. The mixture was extracted with DCM (3×50 mL), the combined organic extract dried and the solvent evaporated. The residue was purified by column chromatography, eluting with 20% EtOAc/pet. ether, to give benzoate 2 (4.12 g, 77%) as a white powder: mp (EtOAc) 127-128° C.; 1H NMR (CDCl3) δ 8.06-8.12 (m, 4 H, H-2, H-3, H-5, H-6), 4.56 (s, 2 H, CH2Cl), 3.94 (s, 3 H, OCH3), 2.45 (s, 3 H, CH3); MS m/z 266.6 (MH+, 100%). Anal. calcd for C13H12C1NO3: C, 58.77; H, 4.55; N, 5.27. Found: C, 58.82; H, 4.43; N, 5.18%.
Reaction SMILES: [N+:1]([O-])(O)=[O:2].N[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:8][C:7]=1[OH:22].[Cl-].[NH4+]>O>[CH3:17][O:16][C:13]1[CH:14]=[C:15]2[C:10]([C:9]([S:18]([O-:21])(=[O:20])=[O:19])=[CH:8][C:7](=[O:22])[C:6]2=[O:2])=[CH:11][CH:12]=1.[NH4+:1]
Reactant: COc1ccc2c(S(=O)(=O)O)cc(O)c(N)c2c1
Reactant: O=[N+]([O-])O
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: COc1ccc2c(c1)C(=O)C(=O)C=C2S(=O)(=O)[O-]
Temperature: 10 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
29.6 ml (0.556 mol) of 70.4%-strength nitric acid were diluted with 82 ml of water. 80.0 g (0.298 mol) of crude 1-amino-2-hydroxy-7-methoxynaphthalene-4-sulfonic acid were added while stirring to this solution of the oxidizing agent at not more than 30° C. in the course of one hour. Stirring was continued for 1 hour, followed by cooling to 10° C., and a solution of 17.6 g of ammonium chloride in 46 ml of water was added. The suspension was cooled to 0° C. for two hours and the product filtered off by suction. The crystals were rinsed first with 25 ml of saturated ammonium chloride solution and then with 40 ml of ethanol. After drying, 77.4 g (91.3%) of crude ammonium 7-methoxy-1,2-naphthoquinone-4-sulfonate were obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][CH:17]2[CH2:26][C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18]2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:28]([O:32][C:33]([N:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[CH2:44]Cl)=[O:34])([CH3:31])([CH3:30])[CH3:29].CCN(C(C)C)C(C)C>CC#N>[C:28]([O:32][C:33]([N:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[CH2:44][N:16]([CH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:27])=[CH:10][CH:11]=1)[CH:17]1[CH2:26][C:25]2[N:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:19][CH2:18]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CNC2CCc3cccnc3C2)cc1
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCc1ccc(CN(Cc2nc3ccccc3n2C(=O)OC(C)(C)C)C2CCc3cccnc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
{4-[(5,6,7,8-Tetrahydro-quinolin-7-ylamino)-methyl]-benzyl}-carbamic acid tert-butyl ester (88 mg, 0.24 mmol), 2-Chloromethyl-benzimidazole-1-carboxylic acid tert-butyl ester (80 mg, 0.30 mmol), DIPEA (0.10 mL, 0.54 mmol), and KI (19 mg, 0.11 mmol) were heated to 80° C. in CH3CN (1.5 mL) for 2 h under N2, then it was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate, washed with NH4Cl (aq), NaCl (aq), and dried (MgSO4). Evaporation of the solvent and purification of the residue by flash chromatography on silica gel (1:1:98 CH3OH—NH3 H2O—CH2Cl2) afforded the title compound (80 mg, 56%) as a white foam.
Reaction SMILES: N1C=CC(OCC#C)=CC=1.[Li]CCCC.[CH3:16][C:17](=[O:38])[C@@H:18]1[C@:35]2([CH3:36])[C@H:21]([C@H:22]3[C@H:32]([CH2:33][CH2:34]2)[C@:30]2([CH3:31])[C@@H:25]([CH2:26][C:27](=O)[CH2:28][CH2:29]2)[CH2:24][CH2:23]3)[CH2:20][CH2:19]1>C1COCC1.C(Cl)Cl>[CH3:16][C:17](=[O:38])[C@@H:18]1[C@:35]2([CH3:36])[C@H:21]([C@H:22]3[C@H:32]([CH2:33][CH2:34]2)[C@:30]2([CH3:31])[C@@H:25]([CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:24][CH2:23]3)[CH2:20][CH2:19]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: C#CCOc1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4CCCC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
A solution of propargyl 4-pyridyl ether (prepared according to (Thummel et al, J. Org. Chem. 1978, 43 4882) (173 mg, 1.3 mmol) in dry THF (15 mL) was treated with n-BuLi (2.5M in THF, 1,3 mmol, 0.52 mL) at −70° C. After stirring the mixture at −75° C. for 0.5 hr, a solution of 5β-pregnan-3,20-dione, cyclic 20-(1,2-ethanediyl acetal) (180 mg, 0.5 mmol) in THF (15 mL) was added and the mixture was stirred at −78° C. for 20 min. The cooling bath was removed and the stirring was continued at rt for 1 hr. The mixture was quenched with NH4Cl solution (2 mL). The solvent was removed and the residue was then dissolved in acetone (25 mL). After adding 2N HCl (2 mL) the s olution was stirred at rt for 20 min. Sat. NaHCO3 soln. was added to neutralize the acid. The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water, and brine. After drying over anhyd. MgSO4 the solution was filtered and evaporated to yield the crude product (250 mg). This crude product was then dissolved in a small amount of CH2Cl2 and poured on a column of silica gel. Elution with CH2Cl2:acetone mixture (90:10) gave 3α-hydrocy-3β-[3-4′-pyridinyloxy)-1-propynyl]-5β-pregnan-20-one (145 mg) as a colorless solid; mp 84-90° C.; TLC Rf (CH2Cl2:acetone 85:15)=0.17.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N(C(C)C)CC)(C)C.CN(C(ON1N=[N:51][C:46]2[CH:47]=[CH:48][CH:49]=[N:50][C:45]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.NC1C=NC=CC=1>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:51][C:46]1[CH:45]=[N:50][CH:49]=[CH:48][CH:47]=1)=[O:9]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cc(Cl)c(C(=O)N2CCOCC2)cc1OCc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1cccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnc1)c1cc(Cl)c(C(=O)N2CCOCC2)cc1OCc1ccccc1
Reaction time: 72 h

Procedure:
To a solution of 5-chloro-4-(4-morpholinylcarbonyl)-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 67; 90 mg, 0.24 mmol) in N,N-dimethylformamide (3 ml) was added diisopropylethylamine (0.08 ml, 0.48 mmol), HATU (164 mg, 0.43 mmol) and 3-aminopyridine (27.0 mg, 0.29 mmol). The solution was stirred for 72 hours. The solvent removed in vacuo and purified by MDAP to give the title compound as a white solid. 55 mg.
Reaction SMILES: Br[CH2:2][CH:3]([F:7])[CH2:4][CH2:5]Br.[C:8]1(=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[NH:9]1.[K]>CN(C)C=O.C(OCC)(=O)C>[F:7][CH:3]([CH2:4][CH2:5][N:9]1[C:10](=[O:17])[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]1=[O:18])[CH2:2][N:9]1[C:10](=[O:17])[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]1=[O:18]
Reactant: FC(CBr)CCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCC(F)CN1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
To a solution of 1,4-dibromo-2-fluoro-butane (4.0 g, 17.09 mmol) in N,N-dimethylformamide (60 mL) was added potassium 2,3-dihydro-1H-isoindole-1,3-dione (9.5 g, 51.27 mmol). The reaction mixture was stirred at 100° C. overnight. The mixture was cooled to room temperature, diluted with ethyl acetate (60 mL), washed with water (60 mL), brine (60 mL), dried over sodium sulfate, and concentrated in vacuo to afford 4.5 g of 2,2′-(2-fluorobutane-1,4-diyl)bis(1H-isoindole-1,3(2H)-dione) as a white solid.
Reaction SMILES: [CH:1]([C:4]1[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]=1[O:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([CH3:21])[CH:20]=1)[CH:16]=O)([CH3:3])[CH3:2].[C:22]([CH2:24]P(=O)(OCC)OCC)#[N:23].CC(C)([O-])C.[K+]>C1COCC1.CC(=O)OCC>[CH:1]([C:4]1[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]=1[O:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:24][C:22]#[N:23])[CH:18]=[C:19]([CH3:21])[CH:20]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(C=O)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C=CC#N)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reaction time: 1 h
Yield: 40 %

Procedure:
To a stirred mixture of 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yloxy)-5-methyl-benzaldehyde (788 mg, 2.73 mmol) and diethyl cyanomethyl-phosphonate (451 μl, 2.79 mmol) in THF (15 ml) at 0° C. (ice bath) under nitrogen atmosphere, was added potassium t-butoxide (920 mg, 8.2 mmol). After stirring for 1 hr., the mixture was stirred for overnight at room temperature. The mixture was then diluted with EA, washed with aqueous saturated ammonium chloride solution, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, EA: hexanes (from 2:3 to 1:1)) to afford 340 mg (40%) of a white solid. m.p. 279-280° C.; 1H NMR (200 MHz, DMSO-d6) δ 1.05 (6H, d, J=7.0 Hz), 2.33 (3H, s), 2.78 (1H, m), 6.55 (1H, d, J=16.8 Hz), 7.03 (1H, s), 7.21 (1H, s), 7.25 (1H, s), 7.62 (1H, d, J=16.8 Hz), 11.05 (1H, s), 11.31 (1H, s); m/z (LC/Mass, EI) 312 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([Cl:17])=[CH:9][CH:8]=2)[NH:4][N:3]=1.[OH-].[Na+].[CH3:20][N:21]=[C:22]=[S:23].O1CCCC1>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:3]([C:22]([NH:21][CH3:20])=[S:23])[N:4]=[C:5]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([Cl:17])=[CH:9][CH:8]=2)[N:6]=1
Reactant: Nc1n[nH]c(-c2ccc(Cl)c3ccccc23)n1
Reactant: CN=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CNC(=S)n1nc(-c2ccc(Cl)c3ccccc23)nc1N
Yield: 5 %

Procedure:
The synthesis method of Example 7-(3) was applied. The compound (2.19 g) obtained in (4) above, a 1N sodium hydroxide solution (10.0 ml), methyl isothiocyanate (1.38 g) and tetrahydrofuran (10 ml) were used as reagents. After the reaction, silica gel column chromatography (chloroform) and recrystallization from chloroform gave 135 mg of white crystals (yield 5% from methyl 4-chloro-1-naphthoate).
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([C:7]2[NH:11][N:10]=[C:9]([C:12]([OH:14])=[O:13])[CH:8]=2)=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH3:21]O>>[C:1]1([CH3:15])[CH:2]=[CH:3][C:4]([C:7]2[NH:11][N:10]=[C:9]([C:12]([O:14][CH3:21])=[O:13])[CH:8]=2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)n[nH]2)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(-c2ccc(C)cc2)[nH]n1
Yield: 84 %

Procedure:
5-p-Tolyl-1H-pyrazole-3-carboxylic acid (250 mg, 1.24 mmol) and sulfuric acid (120 μL, 1.48 mmol) in methanol (5 mL) were heated to reflux for 16 hrs. The solvent was evaporated and the residue was resuspended in CH2Cl2. The residue was filtrated and the filtrate was washed with water and brine and dried over Na2SO4. Solvent was evaporated and the white solid was combined with the precipitate collected previously. Methyl 5-p-tolyl-1H-pyrazole-3-carboxylate (224 mg, 84%) was obtained as a white solid. 1H-NMR (400 MHz, CDCl3): (ppm)=7.56 (d, J=7.6 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 7.02 (s, 1H), 3.91 (s, 3H), 2.36 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1)[NH:11][C:10]([C:18]([O:20]CC)=[O:19])=[CH:9]2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O1CCCC1.[OH-].[Na+]>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1)[NH:11][C:10]([C:18]([OH:20])=[O:19])=[CH:9]2
Reactant: CCOC(=O)c1cc2cc(OCCOC)cc([N+](=O)[O-])c2[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COCCOc1cc([N+](=O)[O-])c2[nH]c(C(=O)O)cc2c1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 97.2 %

Procedure:
Ethyl 5-(2-methoxyethoxy)-7-nitro-1H-indole-2-carboxylate (7.7 g) was dissolved in a mixed solvent of ethanol (75 mL) and tetrahydrofuran (75 mL), 1N aqueous sodium hydroxide solution (75 mL) was added to this solution, and the mixture was stirred at 50° C. for 1.5 hr. Aqueous citric acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The obtained crude product was crystallized from ethyl acetate-hexane to give the title compound (6.8 g, yield 97%) as yellow crystals. melting point 192-193° C.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][C:10](=[O:13])[N:9]1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1c1ccc(F)cn1
Temperature: 120 °C
Yield: 5.9 %

Procedure:
To a pressure tube containing (S)-5-oxo-pyrrolidine-2-carboxylic acid tert-butyl ester (0.5 g, 2.699 mmol), 2-bromo-5-fluoropyridine (0.57 g, 3.239 mmol), cesium carbonate (1.231 g, 3.779 mmol), Xantphos (0.156 g, 0.27 mmol), and tris (dibenzylideneacetone)palladium (0) (0.247 g, 0.27 mmol) is added 13.5 mL degassed anhydrous 1,4-dioxane. The mixture is heated at 120° C. under an atmosphere of Argon overnight. The solution is cooled to room temperature, filtered through Celite®, and concentrated under reduced pressure. The crude material is purified by flash chromatography eluting product with 305 ethyl acetate/heptanes. The product fractions are pooled and concentrated under reduced pressure to afford 45 mg of title compound. Yield 6%. ESI m/z 225=MH+
Reaction SMILES: [CH:1]([CH:13]1[CH2:18][C:17](=[O:19])[O:16][C:14]1=[O:15])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]CCCC.[CH2:20]([NH:23][CH2:24][CH:25]=[CH2:26])[CH:21]=[CH2:22].C1(C)C=CC=CC=1>O>[CH2:20]([N:23]([CH2:24][CH:25]=[CH2:26])[C:17](=[O:19])[CH2:18][CH:13]([CH:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:14]([OH:16])=[O:15])[CH:21]=[CH2:22]
Reactant: CCCCCCCCCCC=CC1CC(=O)OC1=O
Reactant: C=CCNCC=C
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCN(CC=C)C(=O)CC(C=CCCCCCC)C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A 500 ml, two-neck flask was charged with 105.2 g (500 mmol) dodecenylsuccinic anhydride 100 ml toluene. The flask was equipped with a thermometer and immersed in a water bath. Diallylamine (48.6 g, 500 mmol) was then dripped into the magnetically stirred anhydride plus toluene solution over a 15-minute period. Ice was added to the water bath as required to prevent temperature of the reaction mixture from getting above 35° C. The mixture was then stirred for another 45 minutes at room temperature. The toluene was then removed via rotary evaporator and air sparge to yield 153.4 g (99.8% of theory) of a red, oily liquid. An FTIR trace on this compound was found to have significant absorptions at 2924, 1726, 1605, 1440, 1221, 1174, 972, and 922 wavenumbers.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@H:5]23)[CH:10]=1.[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1B(O)O.N>>[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@H:5]23)[CH:10]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(Br)cc3c1N2CC3
Agent: N
Product: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(-c3ccc(Cl)cc3Cl)cc3c1N2CC3
Yield: 50.2 %

Procedure:
The title compound (55.9 mg, 50%) was prepared by the method of Example 89 Step C from tert-butyl(±)-cis-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (94 mg, 0.25 mmol) and 2,4-dichlorophenylboronic acid (95 mg, 0.5 mmol) as a white amorphous solid. MS (CI, NH3): 445 (base, M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH2:14][C:15]([F:18])([F:17])[F:16])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7](OC)=[O:8].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:58][CH2:59][C:60]1[C:61](=[O:68])[NH:62][C:63]([CH3:67])=[CH:64][C:65]=1[CH3:66]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[CH2:14][C:15]([F:16])([F:17])[F:18])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([NH:58][CH2:59][C:60]1[C:61](=[O:68])[NH:62][C:63]([CH3:67])=[CH:64][C:65]=1[CH3:66])=[O:8]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: COC(=O)c1cc(Br)cc(N(CC(F)(F)F)C2CCOCC2)c1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(CC(F)(F)F)C3CCOCC3)c2C)c(=O)[nH]1
Reaction time: 0.08 h
Yield: 74.5 %

Procedure:
A stirred solution of methyl 5-bromo-2-methyl-3-[(oxan-4-yl)(2,2,2-trifluoroethyl)amino]benzoate (250 mg, 0.63 mmol) in dry DMF (3.0 ml) at 0° C. under a balloon of nitrogen, was treated with HATU (288 mg, 0.76 mmol) and DIPEA (220 μl, 1.3 mmol) dropwise. The resulting solution was stirred for 5 minutes and then treated with 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 119 mg, 0.69 mmol). The resulting suspension was stirred at 0° C. for 20 minutes and then stirred at room temperature for 16.5 hours. The reaction mixture was treated with 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (30 mg). Stirring was continued for further 23 hours and the reaction mixture was then partitioned between water (30 ml) and CH2Cl2 (20 ml). The layers were separated and the aqueous phase was extracted with CH2Cl2 (3×20 ml). The combined organics were washed with a saturated solution of NaHCO3 (aq) (50 ml), water (60 ml), brine (2×40 ml), dried over MgSO4, filtered and concentrated in-vacuo. The crude residue was purified by flash column chromatography (10 g SNAP cartridge, Isolera, 0-10% MeOH/CH2Cl2) and triturated from ether (10 ml) with sonication. The resulting precipitate was collected by filtration and dried in-vacuo to give the title compound (249 mg, 74%) as a white solid. LC-MS100%, 4.08 min (7 minute LC-MS method), m/z=530.0, 531.0, 532.0, 533.0; 1H NMR (500 MHz, Acetone) δ 10.67 (s, 1H), 7.55 (d, J=1.8 Hz, 2H), 7.27 (d, J=1.9 Hz, 1H), 5.90 (s, 1H), 4.40 (d, J=5.5 Hz, 2H), 3.90 (dd, J=11.2, 4.6 Hz, 4H), 3.28 (t, J=11.6 Hz, 2H), 3.07-2.97 (m, 1H), 2.32 (s, 3H), 2.29 (s, 3H), 2.24 (s, 3H), 1.76 (dd, J=12.3, 1.6 Hz, 2H), 1.61 (qd, J=12.0, 4.5 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH2:4].Cl[C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[C:18](Cl)[CH:19]=[CH:20][CH:21]=3)[C:16](=[O:27])[C:15]=2[CH:14]=[CH:13][CH:12]=1>[Cu]>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH:4][C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[C:18]([NH:4][C:3]4[CH:5]=[C:6]([Cl:9])[CH:7]=[CH:8][C:2]=4[Cl:1])[CH:19]=[CH:20][CH:21]=3)[C:16](=[O:27])[C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: O=C1c2cccc(Cl)c2C(=O)c2cccc(Cl)c21
Reactant: Nc1cc(Cl)ccc1Cl
Agent: [Cu]
Product: O=C1c2cccc(Nc3cc(Cl)ccc3Cl)c2C(=O)c2cccc(Nc3cc(Cl)ccc3Cl)c21

Procedure:
If, analogously to the above example, 2,5-dichloroaniline is condensed with 1,5-dichloroanthraquinone in the presence of a mixture of 0.5 part of copper powder and 0.5 part of copper-I chloride as the catalyst, instead of the copper-I iodide/picoline complex, only 12 parts of 1,5-bis-(2,5-dichloroanilino)anthraquinone are obtained, corresponding to a yield of only 23%.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[N:11]=[C:10]([N:19]2[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]2)[N:9]=1.C(=O)(O)[O-].[Na+].Cl[C:32]([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:33]>O1CCOCC1>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([CH2:14][S:15]([CH3:18])(=[O:16])=[O:17])[N:11]=[C:10]([N:19]2[CH2:20][CH2:21][CH:22]([NH:25][C:32](=[O:33])[O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:23][CH2:24]2)[N:9]=1
Reactant: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(N2CCC(N)CC2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(N2CCC(NC(=O)Oc3ccccc3)CC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 106.1 %

Procedure:
1-[4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]piperidin-4-amine (500 mg, 1.35 mmol) was dissolved in dioxane (10 mL). Sodium bicarbonate (171 mg, 1.50 mmol) was added. Then phenyl chloroformate (0.171 mL, 1.35 mmol) was added dropwise over 2 minutes. The slurry was stirred at RT for 3 hours. Phenyl chloroformate (0.021 mL, 0.27 mmol) and sodium bicarbonate (21 mg, 0.12 mmol) were added. Stirring at room temp was continued for 1 hour and the reaction mixture evaporated to dryness and partitioned between water (10 mL) and ethyl acetate (10 mL). The water was extracted with a second portion of ethyl acetate (10 mL). The combined organics were dried over magnesium sulfate and evaporated to give the desired material as a foam (701 mg).