Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[N:14]([C:15](OC3C=CC([N+]([O-])=O)=CC=3)=[O:16])[C:13](=[O:27])[NH:12][C:11]([CH2:28][O:29][CH3:30])=[C:10]2[C:31]([O:33][CH3:34])=[O:32])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:35][CH2:36][CH2:37][CH2:38][N:39]1[CH2:44][CH:43]=[C:42]([C:45]2[CH:46]=[C:47]([NH:51][C:52](=[O:54])[CH3:53])[CH:48]=[CH:49][CH:50]=2)[CH2:41][CH2:40]1>>[C:52]([NH:51][C:47]1[CH:46]=[C:45]([C:42]2[CH2:43][CH2:44][N:39]([CH2:38][CH2:37][CH2:36][NH:35][C:15]([N:14]3[C@@H:9]([C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=4)[C:10]([C:31]([O:33][CH3:34])=[O:32])=[C:11]([CH2:28][O:29][CH3:30])[NH:12][C:13]3=[O:27])=[O:16])[CH2:40][CH:41]=2)[CH:50]=[CH:49][CH:48]=1)(=[O:54])[CH3:53]
Reactant: CC(=O)Nc1cccc(C2=CCN(CCCN)CC2)c1
Reactant: COCC1=C(C(=O)OC)[C@H](c2ccc(F)c(F)c2)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1
Product: COCC1=C(C(=O)OC)[C@H](c2ccc(F)c(F)c2)N(C(=O)NCCCN2CC=C(c3cccc(NC(C)=O)c3)CC2)C(=O)N1

Procedure:
Prepared from the reaction of 5-methyl 1-(4-nitrophenyl) (6S)-6-(3,4-difluorophenyl)-4-(methoxymethyl)-2-oxo-3,6-dihydro-1,5(2H)-pyrimidinedicarboxylate (describe in PCT Publication No. WO 00/37026, published Jun. 29, 2000) and N-{3-[1-(3-aminopropyl)-1,2,3,6-tetrahydro-4-pyridinyl]phenyl}acetamide: 1H NMR δ 8.90 (t, 1H, J=3.6 Hz), 7.75 (s, 1H), 7.50-7.00 (m, 8H), 6.68 (s, 1H), 6.03 (br s, 1H), 4.67 (s, 2H), 3.71 (s, 3H), 3.47 (s, 3H), 3.38 (ABm, 2H), 3.16 (m, 2H), 2.71 (t, 2H, J=5.4 Hz), 2.56 (m, 4H), 2.35-1.90 (br, 2H), 2.17 (s, 3H), 1.82 (p, 2H, J=7.2 Hz); ESMS, 612.25 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[N:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1.[NH2:26][CH2:27][CH:28]1[CH2:32][CH2:31][CH2:30][N:29]1[CH2:33][CH3:34].[OH-].[Na+].O>O1CCOCC1.CC(C)=O>[OH-:8].[NH4+:3].[CH:10]1([CH2:9][O:8][C:6]2[N:7]=[C:2]([NH:26][CH2:27][CH:28]3[CH2:32][CH2:31][CH2:30][N:29]3[CH2:33][CH3:34])[N:3]=[C:4]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([F:25])[CH:18]=3)[N:5]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COc1ccc(Nc2nc(Cl)nc(OCC3CCCCC3)n2)cc1F
Reactant: CCN1CCCC1CN
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCN1CCCC1CNc1nc(Nc2ccc(OC)c(F)c2)nc(OCC2CCCCC2)n1
Product: [NH4+]
Yield: 120.2 %

Procedure:
To a sample of 114 (0.3004 g, 0.82 mmol) dissolved in 1,4-dioxane (15 mL) was added a solution of 2-(aminomethyl)-1-ethylpyrrolidine (0.12 mL, 0.82 mmol) in acetone (1 mL) followed by the addition of NaOH (0.33 mL, 2.5 N, 0.82 mmol) and water (1 mL). The reaction mixture was allowed to stir at reflux for about 2 hours under nitrogen. The reaction mixture was extracted 3 times with dichloromethane; the combined organic layers were washed with brine and dried over potassium carbonate. The sample was concentrated on the rotary evaporator and the resulting solid was dried overnight under vacuum. Column chromatography (silica gel, 93:6:1 dichloromethane:methanol:conc. ammonium hydroxide) yielded a light yellow solid, compound 116 (226 mg, 60%), mp 59° C.; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH2PO4 (0.01 M, pH 3.2): CH3OH:CH3CN], 264 nm, Rt 10.5 min, 100% purity; 1H NMR (600 MHz, CDCl3, 55° C.) δ7.65 (broad resonance, rotamers, 1H), 7.07 (br d, J=7.8 Hz, 1H), 6.90 (t, J=9 Hz, 1H) 6.84 (broad resonance, rotamers, 1H), 4.12 (s, 2H), 3.88 (S, 3H), 1.02 (s, 1H), 2.26 (apt sextet, J=6.6 Hz, 1H), 2.19 (q, J=9Hz, 1H), 1.16-1.92 (m, 10H), 1.57 (s, 2H), 1.17-1.32 (m, 3H), 1.05-1.11 (m, 4H); MS (ESI): m/z 459 (M+H, 100), 363 (40.7), 223 (16.1), 202 (4.4), 138 (1.2).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([NH2:16])[CH:7]=1)[CH3:2].[N:18]([O-])=O.[Na+].O.O.[Cl:24][Sn]Cl>Cl>[ClH:24].[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([NH:16][NH2:18])[CH:7]=1)[CH3:2]
Reactant: Cl[Sn]Cl
Reactant: CCOC(=O)Cc1cc(N)cc2ccccc12
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)Cc1cc(NN)cc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
To a mixture of (3-aminonaphthalen-1-yl)acetic acid ethyl ester (2.7 g, 11.8 mmol) in conc. HCl (20 mL) was added an aqueous solution of NaNO2 (0.9 g, 13 mmol) dropwise at 0-5° C. The resulting mixture was stirred at 0° C. for 30 min and then treated with a solution of SnCl2.2H2O (5.9 g, 26.2 mmol) in conc. HCl at such a rate that the reaction temperature never rose above 5° C. After the addition was completed, the mixture was stirred for another 2 h at RT. The precipitate was collected by filtration and washed with ethyl ether to afford (3-hydrazinonaphthalen-1-yl)-acetic acid ethyl ester hydrochloride as a brown solid (2.3 g, 80% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([OH:13])[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1.[CH2:26](Br)[CH:27]=[CH2:28]>>[CH2:28]([O:1][C:2]1[CH:12]=[C:11]([O:13][CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH:10]=[C:4]([CH:3]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:27]=[CH2:26]
Reactant: CCOC(=O)c1cc(O)cc(O)c1
Reactant: BrCc1ccc2ccccc2c1
Reactant: C=CCBr
Product: C=CCOc1cc(OCc2ccc3ccccc3c2)cc(C(=O)OCC)c1
Yield: 15 %

Procedure:
Ethyl 3,5-dihydroxybenzoate was reacted in turn with 2-bromomethylnaphthalene and allyl bromide using the conditions described in Example 1 to give ethyl 5-allyloxy-3-(naphth-2-ylmethoxy)benzoate in 15% yield, as an oil. Following the procedures described in the portion of Example 3 which is concerned with the preparation of starting materials the product so obtained was reacted with thiazol-2-yl-lithium to give 5-allyloxy-3-(naphth-2-ylmethoxy)phenyl 2-thiazolyl ketone in 52% yield, m.p. 65°-67° C., and that product was reacted with ethylmagnesium to give the required starting material in 49% yield, as a gum.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[Cl:8][C:9]1[S:13][C:12]([S:14](Cl)(=[O:16])=[O:15])=[CH:11][CH:10]=1.C(N(CC)CC)C>C1COCC1>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[S:14]([C:12]1[S:13][C:9]([Cl:8])=[CH:10][CH:11]=1)(=[O:16])=[O:15]
Reactant: OCCNCCO
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(Cl)s1)N(CCO)CCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.3 %

Procedure:
To a stirred solution of diethanolamine (1.45 g, 13.8 mmol) in THF (20 mL) was added at 0° C. (ice water bath) commercially available 5-chloro-thiophene-2-sulfonyl chloride (1.0 g, 4.61 mmol) and triethylamine (0.71 mL, 5.07 mmol). The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (ethyl acetate/heptane) to yield the title compound (1.15 g, 88%) as a white solid. MS (ISN) 284.3 [(M−H)−], mp 69° C.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH2:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][N:12]2[C:17]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)([CH2:22][CH3:23])[C:18]([O:20][CH3:21])=[O:19].CN1CCOCC1>C(Cl)Cl>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([C:17]([N:12]2[C:13]3[C:9](=[C:8]([NH:7][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:16]=[CH:15][CH:14]=3)[CH:10]=[CH:11]2)([CH2:22][CH3:23])[C:18]([O:20][CH3:21])=[O:19])=[CH:29][CH:28]=1
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(N)cccc21
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(NS(=O)(=O)CC)cccc21
Reaction time: 0.5 h

Procedure:
Ethanesulfonyl chloride (0.26 g, 2 mmol) was added to a stirred solution of methyl 2-(4-amino-1H-indol-1-yl)-2-(4-chlorophenyl)butanoate (0.58 g, 1.7 mmol), as described in Example 3 Step B, and 4-methylmorpholine (0.25 g, 2.5 mmol) in DCM (8 mL) at 0° C. After 30 min, an additional portion of ethanesulfonyl chloride (0.1 g, 1 mmol) was added. After 1 h, the reaction mixture was partitioned between DCM and saturated aqueous ammonium chloride. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (PE: EA=2:1) to afford the title compound. LC/MS m/z=435.1 [M+H]+.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([OH:22])/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[Cl:9].C1(N)CCCCC1.O>CO>[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[CH:12][C:13]([CH:16]([OH:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:15]=2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: O=C(O)/C=C/C(O)c1ccc(-c2ccc(Cl)c(Cl)c2)cc1
Agent: [Na]
Solvent: CO
Solvent: NC1CCCCC1
Solvent: O
Product: O=C(O)CCC(O)c1ccc(-c2ccc(Cl)c(Cl)c2)cc1
Yield: 62 %

Procedure:
Prepared analogous to Example 46 from the sodium salt of the 4-(3',4'-dichloro-4-biphenylyl)-4-hydroxy-crotonic acid in methanol. Yield: 62% of theory. Melting point of the cyclohexylamine salt: 158°-159° C. (from water).
Reaction SMILES: Br[CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][O:5][CH2:4]1.[C-:9]#[N:10].[Na+]>C(O)C>[OH:8][CH2:7][C:3]1([CH2:2][C:9]#[N:10])[CH2:6][O:5][CH2:4]1
Reactant: OCC1(CBr)COC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: N#CCC1(CO)COC1
Temperature: 25 °C

Procedure:
A solution of 42 g (0.23 mol) of [3-(bromomethyl)oxetan-3-yl] methanol (produced according to Example 1) in 420 ml of ethanol was refluxed with 13 g (0.265 mol) of sodium cyanide for 18 hours. After cooling to room temperature, the precipitated sodium bromide was filtered off and the filtrate concentrated by evaporation. The residue was distilled at 0.4 torr. The yield of product as a colorless oil was 16 g (54 percent). The boiling point of the product was 107° C./0.4 torr. Other data concerning the product was:
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[NH2:2].[C:12](O)(=O)/[C:13](=[C:15](\[CH:17]=[O:18])/[Br:16])/[Br:14].Cl>C(O)C.O>[Br:14][C:13]1[CH:12]=[N:2][N:1]([C:3]2[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=2)[C:17](=[O:18])[C:15]=1[Br:16]
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(-n2ncc(Br)c(Br)c2=O)cc1
Yield: 93.1 %

Procedure:
4-Hydrazinobenzoic acid (2.00 g, 13.1 mmol) in ethanol-water (1:1, 20 mL) was stirred with mucobromic acid (2.26 g, 8.76 mmol) and concentrated hydrochloric acid (10 mL) at 70° C. for 2 days. After cooling, the resulting crystals were collected by filtration, washed with ethanol and water and dried under reduced pressure to give the desired product (3.05 g, 62% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[Mg].C(O)(=O)C>CO>[CH3:1][N:2]([CH3:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc2ccc(=O)[nH]c2c1
Agent: [Mg]
Solvent: CO
Solvent: CC(=O)O
Product: CN(C)c1ccc2c(c1)NC(=O)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.9 %

Procedure:
To a solution of 1.0 g (5.7 mmol) of 7-dimethylamino-2-quinolone [A. Rice, Ann. Chim. 48: 958-996 (1958)] in 40 mL of MeOH was added 1.3 g (5.7 mmol) of magnesium. The reaction was warmed gently on a steam bath, and then was allowed to stir for two hours at room temperature. Acetic acid (8 mL) was then added and the solution filtered. The filtrate was concentrated and the residue chromatographed on 220 g of silica gel, eluting with 97.5:2.5 (v/v) CH2Cl2 :MeOH. Fractions 50-60 (12 mL/fraction) were combined and concentrated to yield 0.4 g of the dihydroquinolone as a white solid, m.p. 154°-156° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]2[C:7]([Br:13])=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:4]=2[CH:3]=1.[Li]CCCC.[S:19](=[O:21])=[O:20].[Cl:22]N1C(=O)CCC1=O>C(OCC)C>[Br:13][C:7]1[C:5]2[S:6][C:2]([S:19]([Cl:22])(=[O:21])=[O:20])=[CH:3][C:4]=2[CH:10]=[CH:9][C:8]=1[O:11][CH3:12]
Reactant: COc1ccc2cc(Br)sc2c1Br
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=S=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ccc2cc(S(=O)(=O)Cl)sc2c1Br
Temperature: -75 °C
Reaction time: 1 h

Procedure:
To a solution of 2,7-dibromo-6-methoxy-benzo[b]thiophene (1.1 g, 3.4 mmol) in diethyl ether (40 mL) was added dropwise at −75° C. n-BuLi (1.6N, 2.35 mL, 3.75 mmol). The reaction mixture was stirred at −75° C. for 1 h, then a stream of sulfur dioxide was passed over the surface of the solvent until the reaction was no more exothermic. The suspension was then stirred at rt for 1 h and concentrated under vacuum. The residue was quenched with sat. sodium bicarbonate-solution (30 mL), and at 0-5° C. N-chlorosuccinimide (0.525 g, 3.95 mmol) was added. The mixture was stirred at rt for 1 h, quenched with water, and extracted with ethyl acetate. The organic phases were dried and concentrated. The residue was chromatographed on silica gel using heptane/ethyl acetate as eluent to obtain 7-bromo-6-methoxy-benzo[b]thiophene-2-sulfonyl chloride (0.57 g). MS (EI) m/e 339.9 (M)
Reaction SMILES: [OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.[C:12](=[O:15])([O-])[O-].[K+].[K+].C=O.[CH2:20](Br)[C:21]#[CH:22]>CN(C=O)C.O.C(OCC)(=O)C>[CH2:22]([O:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH2:12][OH:15])[C:21]#[CH:20]
Reactant: C#CCBr
Reactant: Cn1nc(C(F)(F)F)cc1O
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C#CCOc1c(CO)c(C(F)(F)F)nn1C
Temperature: 25 °C
Yield: 49.2 %

Procedure:
In 100 ml of DMF were suspended 16.6 g (0.10 mole) of the 5-hydroxy-1-methyl-3-trifluoromethylpyrazole synthesized in Reference Example 1 and 20.9 g (0.15 mole) of potassium carbonate. In this suspension being stirred at room temperature was placed 4.5 g (0.15 mole) of paraformaldehyde, followed by stirring at the same temperature for 1 hour. Then, 41.8 g (0.30 mole) of potassium carbonate was added. Thereto was dropwise added 23.8 g (0.20 mole) of propargyl bromide. The reaction mixture was heated to 60° C. and stirred for 2 hours to give rise to a reaction. After the reaction, 200 ml of ethyl acetate and 200 ml of water were added. The organic layer, which appeared by phase separation, was separated. The aqueous layer was subjected to re-extraction with 50 ml of ethyl acetate. The two organic layers were combined and washed with 50 ml of water, 30 ml of a saturated aqueous ammonium chloride solution and 30 ml of a saturated aqueous sodium chloride solution in this order. The resulting organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 31.2 g (purity: 36.9%, yield: 49.2%) of a crude solution of title compound. The crude solution was subjected to vacuum distillation to obtain a title compound as a light yellow transparent solution.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][O:51][C:52]1[CH:53]=[C:54]2[C:59](=[CH:60][CH:61]=1)[CH:58]=[C:57]([C:62]1[CH:63]=[C:64]([NH2:68])[CH:65]=[CH:66][CH:67]=1)[CH:56]=[CH:55]2>CN(C=O)C>[CH3:50][O:51][C:52]1[CH:53]=[C:54]2[C:59](=[CH:60][CH:61]=1)[CH:58]=[C:57]([C:62]1[CH:63]=[C:64]([NH:68][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:65]=[CH:66][CH:67]=1)[CH:56]=[CH:55]2
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: COc1ccc2cc(-c3cccc(N)c3)ccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2cc(-c3cccc(NC(=O)c4cc5cccc(OC)c5oc4=O)c3)ccc2c1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
DIEA (0.0115 mL, 0.067 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.013 g, 0.06 mmol) and HATU (0.025 g, 0.067 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(6-methoxy-naphthalen-2-yl)-phenylamine (0.015 g, 0.06 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.023 g of product in 83% yield: LCMS (ESI) m/z 452 (MH+).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=O)[CH:41]=5)[C:36]([CH3:39])=[CH:37][CH:38]=4)=[O:30])[N:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[N:50]1([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>ClCCCl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[N:24]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:53]6[CH2:54][CH2:55][N:50]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:51][CH2:52]6)[CH:41]=5)[CH:34]=4)=[O:30])[CH:26]=[CH:27][CH:28]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C)c(-c3cccc(C=O)c3)c2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C)c(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)n1
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-6-methyl-3-biphenylyl)methyl]-2,6-pyridinedicarboxamide (1.85 g, 2.80 mmol) and 1,1-dimethylethyl 1-piperazinecarboxylate (1.055 g, 5.61 mmol) were dissolved in 1,2-dichloroethane (30 mL) and acetic acid (0.177 ml, 3.08 mmol) was added. The mixture was stirred for 30 minutes and then MP-Triacetoxyborohydride (3.61 g, 8.41 mmol) was added. The mixture was stirred overnight. It was then filtered through a glass fiber filter paper and washed 2× with 20 mL of DCE. The solvent was evaporated and the residue was taken up in methylene chloride and absorbed on Isolute® Sorbent and purified on a Combiflash on an 80 g silica column eluted with 0-10% MeOH/CH2Cl2. Product fractions were combined and concentrated under vacuum to give 1,1-dimethylethyl 4-[(5′-{[({6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinyl}carbonyl)amino]methyl}-2′-methyl-3-biphenylyl)methyl]-1-piperazinecarboxylate (1.8 g, 2.140 mmol, 76% yield) as a white solid. LC-MS m/z 830 (M+H)+, 0.86 min (ret time).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]2[S:7][C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:12][CH:11]=3)=[CH:9][C:5]=2[CH:4]=1.[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]2[S:7][C:8]([C:10]3[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:14][CH:15]=3)=[C:9]([C:31]([C:30]3[CH:34]=[CH:35][C:27]([F:26])=[CH:28][CH:29]=3)=[O:32])[C:5]=2[CH:4]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc2sc(-c3ccc(OCCN4CCCC4)cc3)cc2c1
Product: COc1ccc2sc(-c3ccc(OCCN4CCCC4)cc3)c(C(=O)c3ccc(F)cc3)c2c1

Procedure:
The title compound was prepared by essentially following the procedure detailed in Example 1, Part C, from 5-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (Part C) and 4-fluorobenzoyl chloride. The crude product was purified by flash chromatography (silica gel, 55:42:3 THF-hexanes-Et3N) to afford 2.11 g (4.44 mmol, 71%) of a yellow semi-solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:6]=1[NH2:7].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[S:23]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:22])(=[O:25])=[O:24]
Reactant: Nc1ccc([N+](=O)[O-])cc1OCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOc1cc([N+](=O)[O-])ccc1N
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
To a stirred suspension of 2 (42 g) and triethylamine (30.4 g) in dichloromethane (400 ml) in an ice bath was added dropwise a solution of methanesulfonyl chloride (25.2 g) in dichloromethane (100 ml). The mixture was stirred for 30 min. and the precipitate was collected by filtration and recrystallized from ethyl acetate to give 33.77 g (58%) of 3: mp 132°-135° C.; MS m/e 276 (M+).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:11][C:12](=O)[CH3:13].Cl>C(COC)OC.C(O)C.O>[CH3:13][C:12]1[N:1]=[C:2]2[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=[CH:8][N:9]2[CH:11]=1
Reactant: Nc1ncccc1C=O
Reactant: CC(=O)CBr
Agent: Cl
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: Cc1cn2cccc(C=O)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-aminonicotinaldehyde (92.8 g, 0.76 mol) and bromoacetone (114.5 g, 0.84 mol) in dimethoxyethane (980 ml) is stirred for 2 hr. at room temperature and then heated at 65° with stirring for 14 hr. The solid which separates is isolated by filtration, dissolved in 800 ml absolute ethanol and heated under reflux for 6 hrs. The ethanol solvent isremoved under reduced pressure and the residue treated with 138 ml 6 N hydrochloric acid in 750 ml water for 0.5 hr. The acidic aqueous layer is washed with ether (2×300 ml) and basified with cooling (78 ml 50% sodium hydroxide and 25 g sodium bicarbonate). The aqueous layer is extracted with dichloromethane. The extracts are combined and dried over anhydrous sodium sulfate. Following filtration, the solvent is removed under reduced pressure to afford 2-methyl-8-formylimidazo[1,2-a]pyridine, mp 136°-139.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1.Br[C:17]1[CH:25]=[C:24]2[C:20]([C:21]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][C:22]=3[N:23]2[CH3:26])=[CH:19][CH:18]=1>>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([C:17]2[CH:25]=[C:24]3[C:20]([C:21]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][C:22]=4[N:23]3[CH3:26])=[CH:19][CH:18]=2)[C:11](=[O:15])[CH:10]=1
Reactant: CN1CCc2c(n(C)c3cc(Br)ccc23)C1
Reactant: O=c1cc(-c2ccc(Cl)cc2Cl)cc[nH]1
Product: CN1CCc2c(n(C)c3cc(-n4ccc(-c5ccc(Cl)cc5Cl)cc4=O)ccc23)C1
Product: Cl
Yield: 43.2 %

Procedure:
4-(2,4-Dichlorophenyl)pyridin-2(1H)-one (103 mg, 0.429 mmol) and 7-bromo-2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (120 mg, 0.43 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (44 mg, 21%) as a yellow solid: mp 308-313° C.; 1H NMR (500 MHz, CD3OD) δ 7.77 (d, J=7.0 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.65 (overlapping dd, J=1.1 Hz, 1H), 7.58 (d, J=1.7 Hz, 1H), 7.49 (s, 2H), 7.16 (dd, J=8.3, 1.8 Hz, 1H), 6.70 (d, J=1.5 Hz, 1H), 6.62 (dd, J=7.0, 1.9 Hz, 1H), 4.86 (m, 1H), 4.50 (d, J=15.3 Hz, 1H), 3.89-3.85 (m, 1H), 3.74 (s, 3H), 3.56-3.55 (m, 1H), 3.23-3.20 (m, 2H), 3.16 (s, 3H); ESI MS m/z 438 [M+H]+; HPLC (Method B) 98.5% (AUC), tR=14.3 min.