Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.OC[CH2:24][C:25]1[N:26]([S:34]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)(=[O:36])=[O:35])[C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2>C(Cl)Cl>[Br:20][CH2:24][C:25]1[N:26]([S:34]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)(=[O:36])=[O:35])[C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2
Reactant: BrBr
Reactant: Cc1ccc(S(=O)(=O)n2c(CCO)cc3ccccc32)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2c(CBr)cc3ccccc32)cc1
Reaction time: 1 h
Yield: 74.9 %

Procedure:
To a solution of triphenylphosphine (20.2 g, 77 mmol) in dry CH2Cl2 (80 mL) was added dropwise a solution of bromine (11.9 g, 77 mmol) in dry CH2Cl2 (40 mL). The stirring was continued for one hour and then a solution of compound of step 2 (23.2 g, 77 mmol) in dry CH2Cl2 (40 mL) was added dropwise. The resulting mixture left stirring for 12 hours. After removing the solvent the residue was taken up in ethyl acetate and washed with water. The organic extract was dried over MgSO4 and the solvent evaporated in vacuo. The residue was chromatographed over silica gel using toluene as eluant to give a yellow oil (21.0 g, 75 %); IR (film) 1600 cm-1, MS ((70eV): m/z 363 (M+,12.6), 129 (100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18](O)=[O:19])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.CC[N:24]([CH:28]([CH3:30])C)[CH:25]([CH3:27])C.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC.N1CCCC1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:15][CH:16]([C:18]([N:24]3[CH2:25][CH2:27][CH2:30][CH2:28]3)=[O:19])[CH2:17]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)C1CC(O)(c2ccc(CN3CCCC3)c(F)c2)C1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCNC1
Solvent: C1CCOC1
Product: O=C(C1CC(O)(c2ccc(CN3CCCC3)c(F)c2)C1)N1CCCC1
Reaction time: 1.5 h

Procedure:
A 2-L 3-neck RB flask, equipped a mechanical stirrer, addition funnel and nitrogen gas inlet was charged with Intermediate 9, 3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]-3-hydroxycyclobutanecarboxylic acid (0.135 mol, crude material from the above intermediate), 500 mL of anhydrous THF and DIEA (34.8 g, 0.27 mol). The initially insoluble mixture was stirred for 1.5 h until a uniform suspension formed. Then 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (50% solution in EtOAc, 104.5 mL, 0.164 mol) was added and stirred for 5 min. (NOTE: exotherm was observed, reached ˜45-50° C.). Then pyrrolidine (28.2 mL, 24.0 g, 0.337 mol) was added. (NOTE: more exotherm was observed, reached ˜70-80° C.). The mixture was stirring at RT for 12 h, then evaporated. The residue was mixed with 500 mL of sat. Na2CO3 and 200 mL of water. The mixture was extracted with DCM (5×300 mL), the extract was dried over Na2SO4, evaporated and dried to give 33.4 g (71% for two steps) of pure title compound (LCMS (M+H): 347.1. 1H NMR (300 MHz, CDCl3): δ 7.37 (t, J=7.37 Hz, 1H), 7.17-7.26 (m, 2H), 3.68 (s, 2H), 3.53 (t, J=6.78 Hz, 2H), 3.44 (t, J=6.58 Hz, 2H), 3.03-3.14 (m, 1H), 2.79-2.87 (m, 2H), 2.5-2.6 (m, 6H), 1.87-2.00 (m, 4H), 1.75-1.80 (m, 4H).
Reaction SMILES: C([O:5][C:6](=[O:20])[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:9]1=[O:19])(C)(C)C.[OH:21][CH:22]([CH2:26][C:27](=[O:40])[N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)[C:23](O)=[O:24].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[OH:21][C@@H:22]([CH2:26][C:27](=[O:40])[N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)[C:23]([N:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:6]([OH:5])=[O:20])[C:9](=[O:19])[C@@H:10]1[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:24]
Reactant: COC(=O)C[C@@H]1NCCN(CC(=O)OC(C)(C)C)C1=O
Reactant: O=C(O)C(O)CC(=O)N1CCN(c2ccncc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)C[C@H]1C(=O)N(CC(=O)O)CCN1C(=O)[C@@H](O)CC(=O)N1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 16.1 %

Procedure:
To a suspension of (S)-(3-methoxycarbonylmethyl-2-oxopiperazin-1-yl)acetic acid tert-butyl ester (0.29 g) and 2-hydroxy-4-oxo-4-(4-pyridin-4-ylpiperazin-1-yl)-butanoic acid (0.30 g) in dimethylformamide (15 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.30 g) and the solution was stirred for 24 hours at room temperature. The solution was concentrated to remove dimethylformamide and the residue was purified by means of CHP-20 column chromatography (H2O→30% acetonitrile aqueous solution). To the produced tert-butyl ester derivative (0.20 g) was added trifluoroacetic acid (6 ml) and the solution was stirred for 1 hour at room temperature. The reaction solution was concentrated and the residue was dissolved in water (10 ml), which was purified by means of CHP-20 column chromatography (H2O→5% acetonitrile aqueous solution). The objected fraction was concentrated and subjected to lyophilization to give the titled compound(0.08 g) as a white amorphous powdery product.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11])=O.[CH2:21]([NH2:24])[CH2:22][CH3:23].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[N+:18]([C:17]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])=[CH:4][C:3]=1[CH2:1][NH:24][CH2:21][CH2:22][CH3:23])([O-:20])=[O:19]
Reactant: CCCN
Reactant: N#Cc1cccc(Oc2ccc([N+](=O)[O-])c(C=O)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCNCc1cc(Oc2cccc(C#N)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Under N2, a mixture of 3-(3-formyl-4-nitrophenoxy)-benzonitrile (0.056 mol) and propylamine (0.059 mol) in DCE (450 mL) was stirred at room temperature, and then NaBH(OAc)3 (0.063 mol) was added, and the reaction mixture was stirred overnight at room temperature. A saturated NaHCO3 solution was added, and the layers were separated. The organic layer was dried, filtered off and the solvent was evaporated. The residue was purified over silica gel filter (eluent: 99:1 CH2Cl2:CH3OH). The purest product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:8][CH:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[NH:11][C:10]1=[O:21].C(N(CC)CC)C>CN(C)C=O>[O:21]=[C:10]1[NH:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[NH:14][C:15](=[O:16])[CH:9]1[NH:8][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: NC1C(=O)Nc2ccccc2NC1=O
Reactant: CCCCC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCC(=O)NC1C(=O)Nc2ccccc2NC1=O
Reaction time: 6 h

Procedure:
Add valeryl chloride (3.92 mL, 33.0 mmol) dropwise to a solution of 3-amino-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione (5.74 g, 30.0 mmol) and triethylamine (4.60 mL, 33.0 mmol) in anhydrous dimethylformamide (123 mL) and stir. After 6 hours, concentrate under reduced pressure to a residue and reconstitute the residue in a solution of isopropanol: chloroform (1:3, 500 mL). Stir overnight to give a solid and isolate the solid by suction filtration, washing the solid with dichloromethane. Vacuum dry the solid at ambient temperature 2 hours to afford the title compound. Wash the filtrate with a saturated aqueous solution of sodium bicarbonate (2×200 mL), and filter the extraction mixture to remove salt formed in the wash. Separate the organic phase and wash it with saturated aqueous sodium chloride (150 mL). Back extract the bicarbonate aqueous phase with dichloromethane. Combine all organics, and dry (sodium sulfate), filter, and concentrate under reduced pressure to a residue. Triturate the residue in diethyl ether, filter the resulting solid, and wash it with diethyl ether; repeat 2×. Dry the solid at ambient temperature under vacuum to give the title compound: mass spectrum (APCI, m/e): 276 (M+1); NMR (1H, 300 MHz, DMSO-d): δ 10.68 (s, 2H), 8.23 (d, 1H, J=7.5 Hz), 7.20 (m, 4H), 4.71 (d, 1H, J=7.5 Hz), 2.25 (t, 2H, J=7.5 Hz), 1.43 (m, 2H), 1.25 (m, 2H), 0.83 (t, 3H, J=7.5 Hz).
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3]1.F[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][N:7]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:28])([F:30])[F:29])[CH:20]=2)[CH:2]([CH3:1])[CH2:3]1)=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: CC1CN(C(=O)OCc2ccccc2)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CN(C(=O)OCc2ccccc2)CCN1c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A 1.01 g portion of benzyl 3-methylpiperazine-1-carboxylate synthesized in Reference Example 10, 814 mg of 4-fluoro-2-trifluoromethylbenzonitrile and 2.38 g of potassium carbonate were added to 20 ml of DMF and stirred at 100° C. for 20 hours. This was mixed with water, extracted with ethyl acetate and dried, and then the solvent was evaporated. The resulting residue was purified by a silica gel column chromatography to obtain 440 mg of the title compound from ethyl acetate-hexane (3:1, v/v) eluate.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[CH:7]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]([CH3:14])[CH:8]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][C:4]([O:13][C:12]1[CH:11]=[CH:10][C:9]([CH3:14])=[CH:8][CH:7]=1)=[O:5]
Reactant: O=C(Cl)CCCl
Reactant: Cc1ccc(O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(OC(=O)CCCl)cc1
Reaction time: 24 h
Yield: 54.6 %

Procedure:
3-Chloropropionyl chloride (12.5 ml, 0.131 mol) was added for three minutes to a solution of p-cresol (12.90 g, 0.119 mol) in pyridine (9.5 ml, 0.12 mol) and CH2Cl2 (53 ml) at 0° C. After stirring the reaction mixture for one day at 0° C. to room temperature, solvent was removed by rotary evaporation. The concentrate was treated with brine (50 ml) and 0.5 M citric acid (150 ml) and extracted with EtOAc (3×100 ml). The organic extracts were washed with 100 ml; 1 N HCl, H2O, cold 0.1 N NaOH, H2O and brine. After solvent removal, the residue was purified by silica gel flash column chromatography eluting with 7.5% EtOAc/hexane to give 12.90 g (55%) of 19 as a colorless liquid: NMR δ 2.34 (s, 3H), 3.03 (t, 2H, J=7), 3.86 (t, 2H, J=7), 6.95-7.01 (m, 2H), 7.17 (d, 2H, J=8).
Reaction SMILES: [F:1][C:2]([F:25])([C:6]([F:24])([F:23])[C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[C:3](Cl)=[O:4].[N+:26]([C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][OH:32])([O-:28])=[O:27].C(N(CC)CC)C.Cl.C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]([F:25])([C:6]([F:24])([F:23])[C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[C:3]([O:32][CH2:31][C:30]1[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=1[N+:26]([O-:28])=[O:27])=[O:4]
Reactant: O=[N+]([O-])c1ccccc1CO
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1[N+](=O)[O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 0.5 h

Procedure:
Perfluorooctanoyl chloride (21.6 g, 0.05 mol) was added slowly with stirring to a solution of 2-nitrobenzyl alcohol (7.65 g, 0.05 mol) and triethylamine (5.2 g, 0.05 mol) in 100 ml benzene. During the addition, the temperature was allowed to rise to 50° C. and the triethylamine hydrochloride began to precipitate. After the addition was complete, the reaction was stirred an additional 30 minutes. The reaction was filtered and the filtrate evaporated in vacuo to give an oil which crystallized on cooling in an ice bath (m.p. 34°-35° C.). Benzene washings of the material retained on the filter paper gave a second fraction of oil which crystallized on cooling. Total yield was 11.97 g.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH2:20][C:21]([N:23]2[CH2:29][CH:28]3[CH2:30][CH2:31][CH:25]([CH2:26][CH2:27]3)[CH2:24]2)=[O:22])[C:3]1=[O:32].[C:33](N1C=CN=C1)([N:35]1[CH:39]=[CH:38][N:37]=[CH:36]1)=[O:34].C(OCC)(=O)C>O>[CH:25]12[CH2:31][CH2:30][CH:28]([CH2:27][CH2:26]1)[CH2:29][N:23]([C:21]([CH2:20][N:4]1[C:5]3[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=3[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])=[N:8][CH:2]([NH:1][C:33]([N:35]3[CH:39]=[CH:38][N:37]=[CH:36]3)=[O:34])[C:3]1=[O:32])=[O:22])[CH2:24]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC1N=C(c2ccccc2F)c2ccccc2N(CC(=O)N2CC3CCC(CC3)C2)C1=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CN1C(=O)C(NC(=O)n2ccnc2)N=C(c2ccccc2F)c2ccccc21)N1CC2CCC(CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
A mixture of (3RS)-3-amino-1-[(3-azabicyclo[3.2.2]non-3-yl]carbonylmethyl]-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (1.2 g) and carbonyldiimidazole (895 mg) was stirred at room temperature overnight. Ethyl acetate and water were added to the reaction mixture, and organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The amorphous powder was washed with isopropyl ether to afford (3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-3-(imidazol-1-yl) carbonylamino-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (1.43 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:7](=[O:9])[CH3:8])[S:5][CH:6]=1.FC(F)(F)C(OC1C(OC(=O)C(F)(F)F)=C([I:21])C=CC=1)=O.II>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[I:21][C:6]1[S:5][C:4]([C:7](=[O:9])[CH3:8])=[CH:3][C:2]=1[CH3:1]
Reactant: CC(=O)c1cc(C)cs1
Reactant: O=C(Oc1cccc(I)c1OC(=O)C(F)(F)F)C(F)(F)F
Agent: II
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)c1cc(C)c(I)s1
Reaction time: 2 h
Yield: 66.2 %

Procedure:
Commercially available 1-(4-Methyl-thiophen-2-yl)-ethanone (2.0 g, 14.2 mmol) was combined with bis(trifluoroacetoxy)iodobenzene (6.3 g, 14.2 mmol) and iodine (3.6 g, 14.2 mmol) in CCl4 (30 ml). The purple suspension was stirred for 2 h upon which time the reaction was judged to be complete by HPLC. The reaction was diluted with CH2Cl2 and washed with Na2S2O3 (aq, sat.) until the purple color dissipated. The organics were washed with H2O and brine. The aqueous layers were extracted once with CH2Cl2 and the combined organics were dried (Na2SO4), filtered and concentrated by rotary evaporation to give a yellow residue which was purified by flash column chromatography (hexanes:ethyl acetate gradient 2–50% ethyl acetate) to give 1-(5-Iodo-4-methyl-thiophen-2-yl)-ethanone (2.5 g, 66%) as a solid; MS (ESI) m/z 266.9 (M+H+); 1H NMR (300 MHz, DMSO-d6) δ 7.65 (s, 1H), 2.47 (s, 3H), 2.19 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:21][CH2:22][N:23]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:25]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8]
Reactant: CCOC(=O)CBr
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)ccc1NCC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCC(CNc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 70 °C
Yield: 50.5 %

Procedure:
A solution of 5-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamide from Example 60 (0.5 g, 1.32 mmol) in 30 mL of dimethylformamide was treated with excess ethyl bromoacetate (0.7 mL, 6.60 mmol). After heating at 70° C. for 1 h, triethylamine (0.9 ml, 6.6 mmol) was added dropwise; the reaction mixture was then heated at 70° C. for an additional 30 min, after which it was partitioned between saturated sodium bicarbonate and dichloromethane. The organic extract was concentrated in vacuo, and the residue was applied to a 10 g SCX column which was washed with methanol and eluted with 1 N ammonia in methanol. The yellow fractions were combined and concentrated in vacuo to afford an orange oil, which was subjected to silica gel chromatography. Elution with 9:1 dichloromethane-methanol, then 9:3 dichloromethane-methanol provided 0.31 g (51%) of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]1[C:11]2[N:10]3[C:12]4[CH:21]=[CH:20][N:19]=[CH:18][C:13]=4[C:14]4[CH2:15][CH2:16][CH:17]=[C:8]([C:9]=43)[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3][CH2:2]1.Br[CH2:23][CH:24]=[CH2:25].C(=O)(O)[O-].[Na+].CN(C)C=O>O>[CH2:25]([CH:3]1[CH2:4][C:5]2[CH:6]=[CH:7][C:8]3[C:9]4[N:10]([C:12]5[CH:21]=[CH:20][N:19]=[CH:18][C:13]=5[C:14]=4[CH2:15][CH2:16][CH:17]=3)[C:11]=2[CH2:1][CH2:2]1)[CH:24]=[CH2:23]
Reactant: C1=CC2=C(CCCC2)n2c3c(c4cnccc42)CCC=C13
Reactant: C=CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCC1CCC2=C(C=CC3=CCCc4c3n2c2ccncc42)C1

Procedure:
A mixture of 3.3 g. of the product of Example 1, 1.45 g. of freshly distilled 3-bromopropene and 1.7 g. of sodium bicarbonate is stirred at room temperature, for 24 hours, in 50 ml. dimethylformamide. At the end of this period, the mixture is poured into water, extracted with ether, and the combined extracts are dried and stripped down. The residue is dissolved in benzene, and the resulting solution chromatographed through a column of neutral alumina. The oily residue obtained on stripping down the eluate is recrystallized from isopropyl alcohol to yield 3-allyl-1,2,3,4,8,9-hexahydropyrido[4',3':2,3]indolo[1,7-ab][1]benzazepine m.p. 112°-113°.
Reaction SMILES: CN(C)CCO.C([Li])CCC.[C:12]1([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Br)(Br)(Br)[Br:25]>CCCCCC.O>[Br:25][C:22]1[CH:23]=[C:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:19]=[CH:20][N:21]=1
Reactant: c1ccc(-c2ccncc2)cc1
Reactant: BrC(Br)(Br)Br
Agent: CN(C)CCO
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Product: Brc1cc(-c2ccccc2)ccn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
To a solution of 2-dimethylaminoethanol (5.60 g, 62.8 mmol) in hexane (80 ml) was added dropwise 1.6N hexane solution of n-butyl lithium (78.5 ml, 125 mmol) under ice-cooling, and stirred at 0° C. for 30 minutes. Then, 4-phenylpyridine (3.24 g, 20.8 mmol) was added thereto, and stirred at 0° C. for 1 hour. After cooling the reaction solution to −78° C., a solution of carbon tetrabromide (25.0 g, 75.4 mmol) in hexane (40 ml) was added thereto, and stirred at −78° C. for 1 hour, then at room temperature for 1 hour. To the reaction solution was added water under ice-cooling, and extracted with ether. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduce pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the titled compound 2.21 g (45.4%) as solid product.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[C:14]([F:17])([F:16])[F:15].[I:18]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C.O>[F:6][C:7]1[C:8]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:10]([OH:13])=[C:11]([I:18])[CH:12]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1ccc(F)c(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Oc1cc(C(F)(F)F)c(F)cc1I
Reaction time: 1 h
Yield: 119.2 %

Procedure:
Concentrated sulfuric acid (0.78 mL. 15.0 mmol) was added to a mixture of 4-fluoro-3-(trifluoromethyl)phenol (8.00 g, 44.4 mmol) and N-iodosuccinimide (5.00 g, 22.2 mmol) in acetic acid (40 mL) at 0° C. After 1 hour, the ice bath was removed and an additional portion of N-iodosuccinimide (1.50 g. 6.67 mmol) added. After an additional 1 hour at ambient temperature, the final portion of N-iodosuccinimide (1.0 g, 4.4 mmol) was added. The reaction mixture was stirred for 1 hour then diluted with water (300 mL), treated with 20 wt % aqueous sodium thiosulfate, and extracted with ether (3×100 mL). The combined organic layers were washed with aqueous sodium thiosulfate then brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by automated silica gel flash chromatography (100% hexanes to 50% dichloromethane in hexanes gradient elution) to afford the title compound as a yellow oil (8.1 g).
Reaction SMILES: [NH2:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][C:3]1=[O:13].[C:14]1(=O)[CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:14]1([NH:1][N:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([OH:12])=[CH:4][C:3]2=[O:13])[CH2:17][CH2:16][CH2:15]1
Reactant: O=C1CCC1
Reactant: Nn1c(=O)cc(O)c2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=c1cc(O)c2ccccc2n1NC1CCC1
Reaction time: 48 h
Yield: 59.9 %

Procedure:
A solution of 1-amino-4-hydroxyquinolin-2(1H)-one (0.516 g, 2.9 mmol) and cyclobutanone (1.05 g, 15.0 mmol) in acetic acid (0.90 g, 15.0 mmol) and methanol (20 mL) was treated portion wise with sodium cyanoborohydride (0.94 g, 15.0 mmol), stirred for 48 hours and concentrated. The residue was treated with 0.5 M aqueous sodium bicarbonate, acidified to pH 2 with 1 M hydrochloric acid and extracted with ethyl acetate. The ethyl acetate was washed with brine, dried over sodium sulfate, filtered and concentrated, The crude material was chromatographed on silica gel eluting with 3:2 hexane/ethyl acetate to give 1-(cyclobutylamino)-4-hydroxyquinolin-2(1H)-one (0.400 g, 60%). MS (ESI+) m/z 231 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ 1.52 (m, 1H) 1.63 (m, 1H) 1.96 (m, 4H) 3.64 (m, 1H) 5.91 (s, 1H) 6.26 (d, J=6.62 Hz, 1H) 7.20 (t, J=8.09 Hz, 1H) 7.61 (m, 1H) 7.84 (m, 2H) 11.42 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C@H:5](O)[CH2:4][C@H:3]1[C:9]1[CH:14]=[CH:13][CH:12]=[N:11][CH:10]=1.C1(=O)OC(=O)CC1.N1C=CC=CC=1>CN(C)C=O>[CH3:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C@H:3]1[C:9]1[CH:14]=[CH:13][CH:12]=[N:11][CH:10]=1
Reactant: CN1C(=O)[C@H](O)C[C@H]1c1cccnc1
Agent: O=C1CCC(=O)O1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CN1C(=O)CC[C@H]1c1cccnc1
Reaction time: 8 h

Procedure:
Cotinine hemisuccinate was prepared by dissolving 19 mg of trans-3'-hydroxycotinine in 1 ml of dimethylformamide (Aldrich). 21 mg of succinic anhydride (Aldrich) were added, followed by 15 μl of pyridine (Aldrich). The mixture was incubated overnight at 45° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH2:24][CH:25]([CH3:27])[CH3:26])[NH:14][C:13](=[O:28])[N:12]=3)[CH:9]=2)[NH:4][N:3]=1.C=O.[C:31]([BH3-])#N.[Na+]>C(O)(=O)C.CN(C)C=O>[CH3:31][NH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH2:24][CH:25]([CH3:26])[CH3:27])[NH:14][C:13](=[O:28])[N:12]=3)[CH:9]=2)[NH:4][N:3]=1
Reactant: CC(C)COc1ccccc1-c1cc(-c2ccc3[nH]nc(N)c3c2)nc(=O)[nH]1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CNc1n[nH]c2ccc(-c3cc(-c4ccccc4OCC(C)C)[nH]c(=O)n3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.7 %

Procedure:
To a 5 mL round bottom flask were added commercially available 4-(3-amino-1H-indazol-5-yl)-6-(2-isobutoxyphenyl)pyrimidin-2(1H)-one (100 mg, 0.26 mmol), formaldehyde (0.12 g of 37% H2O solution, 1.6 mmol), dimethylformamide (2 mL) and glacial acetic acid (1 drop). The reaction mixture was stirred at room temperature for 1 h, after which time sodium cyanoborohydride (1M THF solution (Aldrich), 2 mL, 2 mmol) was added. The reaction mixture was stirred at room temperature for an additional 1 h. Formation of product was confirmed by LC/MS and the product was purified by preparatory HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) to yield 25 mg (25%) of the title compound. 1H-NMR (400 MHz, d6-DMSO): δ 11.78 (s, 1H), 8.62 (s, 1H), 8.04 (d, 1H), 7.61 (d, 1H), 7.49 (t, 1H), 7.30 (d, 1H), 7.19 (d, 1H), 7.10 (m, 2H), 6.23 (q, 1H), 3.85 (d, 2H), 2.86 (d, 3H), 2.01 (m, 1H), 0.93 (d, 6H). MS (EI) for C22H23N5O2: 390 (MH+).