Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([O:18]C)=[O:17])[C:8](=[O:24])[C:7]=1[Br:25].[OH-].[Na+].CC#N.Cl>O>[F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([OH:18])=[O:17])[C:8](=[O:24])[C:7]=1[Br:25]
Reactant: COC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(C(=O)O)cc1-n1c(C)cc(OCc2ccc(F)cc2F)c(Br)c1=O
Temperature: 60 °C
Yield: 87.1 %

Procedure:
Methyl 3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)-4-methylbenzoate (3) (3.4 kg, 7.1 moles), 2.5M NaOH (3.1 L. 7.8 moles), CH3CN (12 L) and 8.6 L water were mixed together and heated to 60° C., under nitrogen. Once the mixture became homogeneous the mixture was stirred for an additional hour. The reaction mixture was cooled to 20° C. and then treated with 865 ml concentrated HCl at a rate such that the temperature was maintained below 25° C. After the HCl addition was completed the mixture was stirred for another hour. The product was filtered and washed with 12 L CH3CN, dried to give 2.87 kg (87%) adduct. 1H NMR (300 MHz, CD3OD) δ 7.87 (dd, J=7.8, 1.6 Hz, 1H), 7.82 (d, J=1.8 Hz, 1H), 7.69 (q, J=8.1 Hz, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.09 (dt, J=2.2, 8.6 Hz, 1H), 6.7 (s, 1H), 5.4 (s, 2H), 2.14 (s, 3H), 2.02 (s, 3H) (d, J=2.4 Hz, 1H), 3.94 (s, 3H), 2.15 (s, 3H), 1.91 (s, 3H). ES-HRMS m/z 464.0275 (M+H calcd for C21H17BrF2NO4 requires 464.0304). Anal. Cald. for C21H16BrF2NO4: C, 54.33; H, 3.47; N, 3.02. Found: C, 54.40; H, 3.42; N, 3.17
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[NH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[I:24].Br[CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29]>O1CCCC1.CCCCCC.[Cl-].[Na+].O>[I:24][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:14]=1[NH:13][CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])[C:18]([O:20][CH3:21])=[O:19]
Reactant: CC(C)=CCBr
Reactant: COC(=O)c1ccc(N)c(I)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NCC=C(C)C)c(I)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of diisopropylamine (2.8 ml) in tetrahydrofuran (25 ml), under nitrogen, cooled to −10° C. was treated with butyl lithium in hexane (12.4 ml, 1.6M). The solution was added slowly via a syringe to a cooled to solution of methyl 4-amino-3-iodobenzoate (5 g, prepared according to the procedure of M. L. Hill, Tetrahedron, 1990, 46, page 4587) in tetrahydrofuran (100 ml), under nitrogen and at −78° C. The mixture was allowed to warm to 0° C. and after stirring for a further 10 minutes the mixture was cooled to −78° C. and then treated with 4-bromo-2-methyl-2-butene (2.49 ml). The reaction mixture was allowed to warm to room temperature over 1.5 hours then poured into saturated brine (100 ml). The organic layer was separated and the aqueous phase was extracted with ethyl acetate (100 ml). the combined organic phases were evaporated and the residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and petroleum ether (1:9, v/v) to give the title compound (5 g).
Reaction SMILES: [CH:1](NC(C)C)(C)C.CCCCCC.C([Li])CCC.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]=1.CI>O1CCCC1.O>[Cl:19][C:20]1[C:25]([CH3:1])=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[N:21]=1
Reactant: FC(F)(F)c1cccc(Cl)n1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CI
Product: Cc1ccc(C(F)(F)F)nc1Cl
Reaction time: 0.33 h

Procedure:
To a solution of diisopropylamine (1.42 mL) in tetrahydrofuran (15 mL) was added dropwise 1.6 M n-butyl lithium-n-hexane solution (6.37 mL) cooled in a dry ice-acetone bath under argon atmosphere, and the mixture was stirred at the same temperature for 20 minutes. Thereto was added dropwise a solution of 2-chloro-6-(trifluoromethyl)pyridine (1.81 g) in tetrahydrofuran (5 mL), and the mixture was stirred for 2 hours. To the reaction mixture was added methyl iodide (0.69 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with diethylether. The organic layer was washed successively with 0.5N HCl, water, an aqueous saturated sodium hydrogencarbonate solution and bribe, dried over sodium sulfate and concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (Solvent; n-hexane→n-hexane/ethyl acetate=90/10) to give 2-chloro-3-methyl-6-(trifluoromethyl)pyridine (0.90 g) as a yellow powder.
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].C(O)=O.[NH2:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:13]=1[C:14]#[N:15].CCN(CC)CC>C(Cl)Cl>[S:2]([NH:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[C:13]=1[C:14]#[N:15])(=[O:4])(=[O:3])[NH2:5]
Reactant: COc1ccc(COc2cccc(N)c2C#N)cc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O=CO
Solvent: CCN(CC)CC
Product: COc1ccc(COc2cccc(NS(N)(=O)=O)c2C#N)cc1
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a solution of chlorosulfonyl isocyanate (212 mg, 1.50 mmol) in CH2Cl2 (0.55 mL) at 0° C., was added formic acid (0.575 mL) under N2. The reaction was stirred for 30 min, and a solution of 2-amino-6-(4-methoxybenzyloxy)benzonitrile (Example 114b) (191 mg, 0.75 mmol) in CH2Cl2 (4 mL) was added at 0° C., followed by Et3N (0.627 mL, 4.50 mmol). After 30 min, the reaction was concentrated in vacuo and diluted with water. The pH was adjusted to 7 with concentrated HCl, and purified by reverse phase HPLC (10-90% acetonitrile in water) to provide 2-sulfamoylamino-6-(4-methoxybenzyloxy)benzonitrile (130 mg, 52%). 1H NMR (400 MHz, MeOD) δ 3.80 (s, 3H), 5.15 (s, 2H), 6.88 (d, J=8.1 Hz 1H), 6.94 (m, 2H), 7.40 (m, 2H), 7.48 (t, J=8.7 Hz, 1H), 7.75 (dd, J=8.6, 0.8 Hz, 1H).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][S:8]2(=[O:17])=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:38][CH2:39][CH:40]1[O:45][CH2:44][CH2:43][N:42](C(OC(C)(C)C)=O)[CH2:41]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[NH:42]1[CH2:43][CH2:44][O:45][CH:40]([CH2:39][CH2:38][N:9]2[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[S:8]2(=[O:16])=[O:17])[CH2:41]1
Reactant: O=S1(=O)Nc2ccccc2N1c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCOC(CCO)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=S1(=O)N(CCC2CNCCO2)c2ccccc2N1c1ccccc1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution of 1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.2 g, 0.8 mmol) in THF (10 mL) was added triphenylphosphine (0.26 g, 1 mmol), tert-butyl 2-(2-hydroxyethyl)morpholine-4-carboxylate (0.2 g, 0.9 mmol) and DIAD (0.2 g, 1 mmol) at 0° C. The mixture was allowed to warm to ambient temperature overnight then concentrated and chromatographed on silica gel (0 to 40% EtOAC in hexane). The resulting mostly pure carbamate was dissolved in dichloromethane (10 mL) and treated with HCL (4 mL, 4M in dioxane). The resulting salt was chromatographed on silica (0 to 100% of (7N NH3/MeOH) in dichloromethane) giving the desired product as a clear oil (0.23 g, 80%). HRMS: calcd for C18H21N3O3S+H+, 360.1376; found (ESI, [M+H]+), 360.1377.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17]C)[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:33]=[CH:32][C:23](/[CH:24]=[CH:25]/[C:26]3[O:27][C:28]([CH3:31])=[N:29][N:30]=3)=[CH:22][CH:21]=2)=[C:4]([CH3:34])[CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:21]=[CH:22][C:23](/[CH:24]=[CH:25]/[C:26]3[O:27][C:28]([CH3:31])=[N:29][N:30]=3)=[CH:32][CH:33]=2)=[C:4]([CH3:34])[CH:3]=1
Reactant: COc1ccc2c(Oc3ccc(/C=C/c4nnc(C)o4)cc3)c(-c3ccc(F)cc3C)sc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1nnc(/C=C/c2ccc(Oc3c(-c4ccc(F)cc4C)sc4cc(O)ccc34)cc2)o1
Temperature: 25 °C
Yield: 26.2 %

Procedure:
To a 30 mL screw cap vial, (E)-2-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)styryl)-5-methyl-1,3,4-oxadiazole (12 mg, 0.025 mmol) was dissolved in DCM (0.5 mL). The vial was charged with BBr3 (1.0 M in hexanes, 0.076 ml, 0.076 mmol) and the reaction mixture was stirred for 1 b at room temperature. The reaction mixture was quenched with 2 mL MeOH and stirred for 10 min. The mixture was concentrated onto silica gel and the crude material was purified by reverse phase HPLC (acidic condition, 0.1% TFA in 30-100% CH3CN/H2O) to afford (E)-2-(4-fluoro-2-methylphenyl)-3-(4-(2-(5-methyl-1,3,4-oxadiazol-2-yl)vinyl)phenoxy)benzo[b]thiophen-6-ol (3 mg, 6.54 μmol, 26% yield) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ ppm=2.26 (s, 3 H), 2.45 (s, 3 H), 6.73-6.86 (m, 5 H), 6.88 (dd, J=9.85, 2.78 Hz, 1 H), 7.08-7.30 (m, 3 H), 7.34-7.45 (m, 3 H), LC/MS (m/z, MH+): 459.4.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH2:7][N:8]([CH2:24][CH2:25][O:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:9]1[C:10]([N+:21]([O-:23])=[O:22])=[CH:11][C:12]([N+:18]([O-:20])=[O:19])=[C:13]([CH:17]=1)[C:14]([OH:16])=O)(=[O:4])=[O:3].[NH2:31][CH2:32][CH2:33][OH:34].Cl>O=S(Cl)Cl.CN(C=O)C>[CH3:1][S:2]([O:5][CH2:6][CH2:7][N:8]([CH2:24][CH2:25][O:26][S:27]([CH3:30])(=[O:28])=[O:29])[C:9]1[CH:17]=[C:13]([C:14]([NH:31][CH2:32][CH2:33][OH:34])=[O:16])[C:12]([N+:18]([O-:20])=[O:19])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22])(=[O:3])=[O:4]
Reactant: NCCO
Reactant: CS(=O)(=O)OCCN(CCOS(C)(=O)=O)c1cc(C(=O)O)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CS(=O)(=O)OCCN(CCOS(C)(=O)=O)c1cc(C(=O)NCCO)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 82.2 %

Procedure:
A suspension of 8 (3.20 g, 6.79 mmol) in SOCl2 (60 mL) containing DMF (2 drops) was heated under reflux for 1 h. Evaporation of the solvent under reduced pressure, followed by azeotroping in with benzene gave the crude acid chloride, which was dissolved in dry Me2CO (80 mL) and treated at 0° C. with 2-aminoethanol (1.24 g, 20.3 mmol). After stirring at 0° C. for 5 min, the mixture was acidified to pH 2-3 with 0.2 N HCl, concentrated to half volume, and then solid NaBr was added. The mixture was extracted with EtOAc (2×) and the combined extracts were washed with saturated NaBr solution, dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel, eluting with EtOAc/MeOH (15:1) to give 2-(5-{[(2-hydroxyethyl)amino]carbonyl} {2-[(methylsulfonyl)oxy]ethyl}-2,4-dinitroanilino)ethyl methanesulfonate (9a) (2.87 g, 82%) as a gum that was used directly.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1.[Cu].S([O-])([O-])(=O)=O.[Cu+2]>[O:9]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][CH:6]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Brc1ccccc1
Reactant: COc1cccc(O)c1
Agent: [Cu+2]
Agent: [Cu]
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Product: COc1cccc(Oc2ccccc2)c1
Yield: 75 %

Procedure:
3-Methoxyphenol (287.4 g; 2.3 Mol), 316.0 g (2.0 Mol) of bromobenzene, 552 g (4.0 Mol) of K2CO3, 12.0 g (0.19 Mol) of activated copper (prepared according to Org. Syn. Coll. Vol. II, p 445-6), Cu(II) acetate hydrate 2.0 g (11 mMol), CuO powder (2.0 g; 25 mMol), and 2.0 g of copper sulfate (13 mMol) were combined in 1500 mL of dry pyridine. The resultant mixture was heated under reflux for 3 days. After cooling, the mixture was concentrated under reduced pressure, then treated with 6N HCl. Extraction was carried out with ether. The combined organics were washed with water, dilute NaOH, and water, then concentrated under reduced pressure. The residue was distilled in vacuo to give 3-phenoxyanisole, distilling at 138-40° C./2 mm pressure, 119 g (75% yield). H1NMR (CDCl3) d: 3.81 (s, 3 H), 6.61 (m, 2 H), 6.68 (d, J=7.8 Hz, 1 H), 7.06 (d, J=8.3, 2 H), 7.14 (t, J=7.4 Hz, 1 H), 7.25 (t, J=8.4 Hz, 1 H), 7.37 (t, J=7.8 Hz, 2 H).
Reaction SMILES: [C:1]([S:4][CH:5]([CH:18]([C:23]([NH:25][C@H:26]([C:36]([NH:38][CH3:39])=[O:37])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:6][C:7]([NH:9][CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])=[O:8])(=[O:3])[CH3:2]>FC(F)(F)C(O)=O.O>[C:1]([S:4][CH:5]([CH:18]([C:23]([NH:25][C@H:26]([C:36]([NH:38][CH3:39])=[O:37])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:6][C:7]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])(=[O:3])[CH3:2]
Reactant: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)C(CC(=O)NCC(=O)OC(C)(C)C)SC(C)=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)C(CC(=O)NCC(=O)O)SC(C)=O
Reaction time: 2 h

Procedure:
A solution of 2-[3-acetylmercapto-6-methyl-4-[[[1-(S)-[(methylamino)carbonyl]-2-(4-methoxyphenyl)ethyl]amino]carbonyl]heptanoylamino]ethanoic acid, t-butyl ester (E12, Isomer A; 60 mg, 0.11 mmol) in trifluoroacetic acid (1.5 ml) and water (0.05 ml) was stirred in an ice bath for 1 h, then at room temperature for 2 h. The solvent was evaporated in vacuo and the residue was azeotroped dry with toluene to leave the title compound as a single isomer (Isomer A), mp 188°-192° C.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[C:23]([C:27]1[CH:28]=[C:29]([CH2:66][OH:67])[C:30]([O:64][CH3:65])=[C:31]([NH:33][C:34]([C:36]2[CH:37]=[CH:38][C:39]([CH3:63])=[C:40]([CH:62]=2)[O:41][C:42]2[CH:47]=[CH:46][N:45]=[C:44]([CH2:48][CH:49]3[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]3)[CH:43]=2)=[O:35])[CH:32]=1)([CH3:26])([CH3:25])[CH3:24]>ClCCl>[C:23]([C:27]1[CH:28]=[C:29]([CH:66]=[O:67])[C:30]([O:64][CH3:65])=[C:31]([NH:33][C:34]([C:36]2[CH:37]=[CH:38][C:39]([CH3:63])=[C:40]([CH:62]=2)[O:41][C:42]2[CH:47]=[CH:46][N:45]=[C:44]([CH2:48][CH:49]3[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:59])([CH3:60])[CH3:61])=[O:56])[CH2:51][CH2:50]3)[CH:43]=2)=[O:35])[CH:32]=1)([CH3:24])([CH3:25])[CH3:26]
Reactant: COc1c(CO)cc(C(C)(C)C)cc1NC(=O)c1ccc(C)c(Oc2ccnc(CC3CCN(C(=O)OC(C)(C)C)CC3)c2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1c(C=O)cc(C(C)(C)C)cc1NC(=O)c1ccc(C)c(Oc2ccnc(CC3CCN(C(=O)OC(C)(C)C)CC3)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
120 mg of 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (“Dess-Martin-Periodinane”) are added to an ice-cooled solution of 200 mg of tert-butyl 4-{4-[5-(5-tert-butyl-3-hydroxymethyl-2-methoxy-phenylcarbamoyl)-2-methyl-phenoxy]-pyridin-2-ylmethyl}-piperidine-1-carboxylate in 6 ml dichloromethane. The cooling bath is removed, and the solution is stirred overnight at ambient temperature. Then the solution is diluted with dichloromethane and washed with aqueous K2CO3 solution and aqueous Na2S2O3 solution. The organic phase is dried (Na2SO4) and the solvent is removed. The residue is chromatographed on silica gel with dichloromethane/methanol (99:1→90:10) as eluant.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[CH3:21][C:22]1[CH2:26][C:25](=[O:27])[N:24]([C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)[N:23]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:20][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:28]([N:24]2[C:25](=[O:27])[CH2:26][C:22]([CH3:21])=[N:23]2)=[CH:29][CH:30]=1
Reactant: CC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1
Reactant: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1N
Product: CC1=NN(c2ccc(C(=O)Nc3ccc(N4CCC(CN5CCCC5C)C4)cc3C)cc2)C(=O)C1

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylamine with 4-(3-methyl-5-oxo-4,5-dihydro-pyrazol-1-yl)-benzoic acid. MS: 474.6 (M+H).
Reaction SMILES: [N:1]1([C:4]2[C:5]3[N:13]([CH2:14][CH3:15])[N:12]=[C:11]([CH3:16])[C:6]=3[N:7]=[C:8]([CH3:10])[N:9]=2)[CH2:3][CH2:2]1.[I-].[Na+]>CC(C)=O>[CH2:14]([N:13]1[C:5]2[C:4]3[N:9]([CH2:2][CH2:3][N:1]=3)[C:8]([CH3:10])=[N:7][C:6]=2[C:11]([CH3:16])=[N:12]1)[CH3:15]
Reactant: CCn1nc(C)c2nc(C)nc(N3CC3)c21
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCn1nc(C)c2c1C1=NCCN1C(C)=N2
Reaction time: 8 h
Yield: 56.6 %

Procedure:
The above aziridine (14 g, 0.065 mol) is dissolved in 150 ml acetone and 12 g (0.08 mol) of sodium iodide is added. The mixture is stirred overnight as a solid separates. The cooled mixture is filtered, the filter cake is washed with saturated NaHCO3 solution then water to yield 8 g (57%) of the title compound, mp 168°-170° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([I:18])=[N:13][C:14]([I:17])=[CH:15][CH:16]=1)(C)(C)C.Cl.O1CCOCC1>ClCCl>[I:18][C:12]1[C:11]([O:10][CH2:9][CH2:8][NH2:7])=[CH:16][CH:15]=[C:14]([I:17])[N:13]=1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(I)nc1I
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCCOc1ccc(I)nc1I

Procedure:
To a solution of 4-2 (2.18 g, 4.45 mmol) in dichloromethane (5.0 mL) at room temperature under Ar was added 4.0 M HCl-dioxane solution (25 mL). A white precipitate formed immediately. After two hours the reaction was concentrated and dried to yield a white solid;
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:22][CH:23]2[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[C:12]1[NH:20][C:19]2[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=2[CH:13]=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:3]([NH:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:11]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1CCNCC1
Reaction time: 0.5 h
Yield: 6.8 %

Procedure:
A solution of tert-butyl 4-((3-methyl-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxalin-2-yl)amino)piperidine-1-carboxylate (Ex. 47, 80 mg, 0.168 mmol) in DCM (1.7 mL) was stirred at 25° C. before adding TFA (12.47 μl, 0.168 mmol, Sigma Aldrich). The resulting solution was stirred for 30 min before carefully adding saturated aq. NaHCO3 (10 mL) and stirring for an additional 30 min. The reaction mixture was then concentrating under reduced pressure, and the residue was taken up in DMSO and purified by reverse-phase preparative HPLC (Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in ACN/H2O, gradient 5% to 80%). The product-containing fractions were concentrated under reduced pressure, and the residue was loaded onto a pre-washed (MeOH, 1 volume) functionalized Si-carbonate column (Silicyle) and allowed to percolate through, providing 2-(2-methyl-3-(piperidin-4-ylamino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (4.3 mg, 6.8%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.92 (1H, s) 7.83-7.91 (1H, m) 7.52-7.58 (2H, m) 7.28-7.35 (1H, m) 7.11-7.16 (1H, m) 3.98-4.11 (3H, m) 3.41-3.49 (2H, m) 2.97-3.06 (2H, m) 2.89 (2H, s) 2.59-2.71 (2H, m) 2.54 (3H, s) 1.93-2.04 (2H, m) 1.43-1.59 (2H, m). m/z (ESI, +ve) 377.1 (M+H)+.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH:15]3[CH2:27][C:26]4[C:25]5[C:20](=[CH:21][CH:22]=[C:23]([O:28]C)[CH:24]=5)[NH:19][C:18]=4[CH2:17][CH2:16]3)[CH2:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1>C1(C)C=CC=CC=1.C(N(CC)CC)C>[C:2]1([C:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]3[CH2:27][C:26]4[C:25]5[C:20](=[CH:21][CH:22]=[C:23]([OH:28])[CH:24]=5)[NH:19][C:18]=4[CH2:17][CH2:16]3)[CH2:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2[nH]c3c(c2c1)CC(CN1CC=C(c2ccccc2)CC1)CC3
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Oc1ccc2[nH]c3c(c2c1)CC(CN1CC=C(c2ccccc2)CC1)CC3
Reaction time: 3 h

Procedure:
A mixture of 4.19 g of 3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridylmethyl)-6-methoxy-1,2,3,4-tetrahydrocarbazole hydrochloride and 3.5 g of pyridine hydrochloride is stirred at 160° for 3 hours. After the usual work-up, 3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridylmethyl)-6-hydroxy-1,2,3,4-tetrahydrocarbazole, Rf 0.2 (toluene/triethylamine 9:1), is obtained.
Reaction SMILES: C([Mg]Br)C.[CH:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[I:15]I.C(O)(=O)C>CCOCC>[I:15][C:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: C#CCCCCCCCC
Reactant: II
Agent: CC[Mg]Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCCCCCCCC#CI
Temperature: 15 °C
Yield: 90 %

Procedure:
To a 500 ml 3-neck round bottom flask is transferred an ethylmagnesium bromide solution, 100 ml of 3.0M in dried ether, 0.30 mole, under an argon atmosphere. The contents are cooled to about 0° to 3° C. in a solution of 1-decyne, 25 grams, 0.1808 mole, and 50 ml of dried ether are added dropwise into the reaction mixture over a period of 1.5 hours. Thereafter the mixture is warmed to 35°-38° C. and maintained at that temperature for an additional hour. The mixture is then cooled to about 15° C. and powdered iodine, 80 g., 0.315 mole, is slowly added through a solid addition funnel over a period of about 1.5 hours. The reaction is maintained at 30° C. for approximately 2.5 additional hours. In the meantime, an additional 150 ml of dried ether is added to limit the viscosity increase during the reaction. In the work-up process, 200-300 ml of ether are added and the contents hydrolyzed by slowly pouring them into two liters of cold, dilute acetic acid having a pH of about 1-2. The organic phase is extracted with ether and washed several times with 10 percent Na2S2O3 solution to remove the unreacted iodine. Washing continues until the organic phase exhibits a clear color. Following this, the phase is washed several times with water and dried over MgSO4. The solvent is removed by means of a rotary evaporator, and the oily crude product is purified by column chromatography, using silica gel absorbent and hexane as an eluent. The yield is about 90 percent based on 1-decyne used, of a pale yellow liquid, 43.0 grams, 0.1629 mole.
Reaction SMILES: Br[CH2:2][CH:3]1[C:7]2[C:8]([CH3:15])=[C:9]([OH:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:6]=2[O:5][C:4]1([CH3:17])[CH3:16].C1(O)C=CC=CC=1.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C(#N)C>[CH3:16][C:4]1([CH3:17])[CH:3]([CH2:2][N:29]2[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]2)[C:7]2[C:8]([CH3:15])=[C:9]([OH:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:6]=2[O:5]1
Reactant: Cc1c(C)c2c(c(C)c1O)C(CBr)C(C)(C)O2
Reactant: CN1CCNCC1
Solvent: Oc1ccccc1
Solvent: CC#N
Product: Cc1c(C)c2c(c(C)c1O)C(CN1CCN(C)CC1)C(C)(C)O2
Yield: 22.8 %

Procedure:
A solution of 3-bromomethyl-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-ol (81 g, 270 mmol), phenol (26.75 g, 284 mmol) and N-methylpiperazine (28.47 g, 284 mmol) in acetonitrile (300 ml) is stirred at reflux temperature for 60 hrs. The precipitate that formed is collected, washed with acetonitrile and slurtied in 10% sodium bicarbonate solution. The product is extracted twice with ethyl acetate, and the extract is washed with water and brine, dried (sodium sulfate) and evaporated. The resulting solid is dissolved in ethanol (150 mL) and 2N hydrochloric acid (150 mL), and evaporated to near dryness. The resulting solid is recrystallized in ethanol/ethyl acetate to give after drying at 60° C. under 13 Pa and equilibration in a moist atmosphere for 24 hrs, 48.60 g (44%) of 2,2,4,6,7-pentamethyl-3-[(4-methylpiperazino)-methyl]-2,3-dihydro-1-benzofuran-5-ol dihydrochloride hydrate, mp=172°-3° C.(dec.). A second crop of 19.63 g of 2,2,4,6,7-pentamethyl-3-[(4-methylpiperazino)-methyl]-2,3-dihydro-1-benzofuran-5-ol (total yield 63%) could be obtained from the filtrate after purification of the free base by column chromatography on silica gel eluting with dichloromethane/methanol 9:1.