Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[O:4].Cl.[N:18]([O-])=[O:19].[Na+].C(=O)(O)[O-].[Na+]>O>[CH3:1][O:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[N:18]=[O:19])[N:9]([CH2:10][CH3:11])[CH2:12][CH3:13])=[O:4]
Reactant: O=N[O-]
Reactant: CCN(CC)c1cccc(NC(=O)OC)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCN(CC)c1ccc(N=O)c(NC(=O)OC)c1
Yield: 98.8 %

Procedure:
While stirring a mixture of 6.0 g of 3-(methoxycarbonylamino)-N,N-diethylaniline, 10 ml of water, and 2.0 ml of concentrated hydrochloric acid at 0° C, 2.0 g of sodium nitrite was added to the mixture. When the first crystals were deposited in the mixture, 50 ml of water was further added to the mixture followed by stirring for 30 minutes. Thereafter, the reaction mixture obtained was poured into 300 ml of water followed by stirring well, neutralized by the addition of sodium bicarbonate, and extracted with ethyl acetate. After washing with water, the extract was dried by Glauber's salt and the solvent was distilled off using an evaporator to provide a yellow-green oily product. The crude product was purified by silica gel chromatography to provide 6.7 g (yield: 98%) of a product as a green solid.
Reaction SMILES: Br[CH:2]([CH3:6])[C:3](=O)[CH3:4].[NH2:7][C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][N:9]=1.C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[Br:14][C:12]1[CH:11]=[CH:10][N:9]2[C:2]([CH3:6])=[C:3]([CH3:4])[N:7]=[C:8]2[CH:13]=1
Reactant: Nc1cc(Br)ccn1
Reactant: CC(=O)C(C)Br
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1nc2cc(Br)ccn2c1C
Yield: 40.5 %

Procedure:
3 mL (19.86 mmol) of 3-bromobutan-2-one are added to a mixture, stirred at 20° C., of 1.5 g (8.67 mmol) of 2-amino-4-bromopyridine and 1.45 g (17.34 mmol) of sodium hydrogen carbonate in 50 mL of ethanol. The mixture is stirred at reflux for 12 hours and then concentrated under reduced pressure. The mixture obtained is taken up in 20 mL of water. The pH of the solution is basified by successive addition of potassium carbonate. A precipitate is collected by filtration, and is washed with water and then dried under reduced pressure. 0.79 g of the expected product is thus isolated, and is used without further purification in the rest of the synthesis.
Reaction SMILES: [NH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)[NH2:2].[C:16]1([CH:22]([CH:25]=O)[CH:23]=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[C:16]1([C:22]2[CH:23]=[N:2][N:1]([CH:3]3[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]3)[CH:25]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NN)CC1
Reactant: O=CC(C=O)c1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccccc3)cn2)CC1
Temperature: 75 °C
Reaction time: 36 h
Yield: 23 %

Procedure:
To a solution of tert-butyl 4-hydrazinopiperidine-1-carboxylate (646 mg) and ethanol (15 mL) was added phenyl malonaldehyde (444 mg), followed by stirring at 75° C. for about 1.5 days. The reaction liquid was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/chloroform-50/50 to 0/100) to obtain tert-butyl 4-(4-phenyl-1H-pyrazol-1-yl)piperidine-1-carboxylate (226 mg).
Reaction SMILES: [CH2:1]([C:4]12[C:22](=[O:23])[CH:9]3[CH:10]=[C:11]4[C:20]1([CH:7]([CH2:8]3)[CH2:6][O:5]2)[O:19][C:18]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:12]4=[O:21])[CH:2]=[CH2:3].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>O1CCCC1>[CH2:1]([C:4]12[C:22](=[O:23])[CH:9]3[CH2:10][CH:11]4[C:20]1([CH:7]([CH2:8]3)[CH2:6][O:5]2)[O:19][C:18]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:12]4=[O:21])[CH:2]=[CH2:3]
Reactant: C=CCC12OCC3CC(C=C4C(=O)c5ccccc5OC431)C2=O
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC12OCC3CC(CC4C(=O)c5ccccc5OC341)C2=O
Reaction time: 0.42 h
Yield: 39 %

Procedure:
To a stirring solution of 1-allyl-1,3,3a,4,5,12a-hexahydro-7,13-dioxo-1,5-methano-furo[3,4-d]xanthene (29.0 mg, 0.0941 mmol) and tetrahydrofuran (15.0 mL) in a dry ice bath under argon was added dropwise 1.0 M L-Selectride in THF (150 μL, 0.150 mmol) and the solution was stirred for 25 min. The dry ice bath was removed and the solution was stirred for 20 minutes. The solution was concentrated by rotary evaporation and was purified by column chromatography (2:1 hexanes/ethyl acetate) to yield 11.4 mg (39%) of the title compound as a white solid. 1H NMR (CDCl3, 300 MHz): δ 7.91 (dd, J1=8.11 Hz, J2=1.79, 1H), 7.54 (ddd, J1=8.17 Hz, J2=6.94, J3=1.45, 1H), 7.08 (m, 2H), 5.86 (m, 1H), 5.27 (m, 1H), 5.12 (dt, J1=10.16 Hz, J2=1.51, 1H), 4.16 (dd, J1=7.97 Hz, J2=4.12, 1H), 3.53 (d, J=7.96 Hz, 1H), 3.40 (dd, J1=11.54 Hz, J2=3.30, 1H), 3.06 (dd, J1=13.46 Hz, J2=6.04, 1H), 2.87 (dd, J1=13.32 Hz, J2=8.93, 1H), 2.82 (dt, J1=14.28 Hz, J2=3.57, 1H), 2.74 (dd, J1=9.89 Hz, J2=4.39, 1H), 2.44 (m, 1H), 2.01 (dd, J1=13.47 Hz, J2=10.44, 1H), 1.78 (ddt, J1=14.15 Hz, J2=11.67 J3=2.68, 1H), 1.67 (dt, J1=14.10 Hz, J2=3.50, 1H).
Reaction SMILES: Br.[NH2:2][C:3]1[N:4]([CH2:17][C:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])([CH3:20])[CH3:19])[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[C:7](Cl)[C:6]=2[N:16]=1.[NH3:26]>CO>[NH2:2][C:3]1[N:4]([CH2:17][C:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])([CH3:20])[CH3:19])[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([NH2:26])[C:6]=2[N:16]=1
Reactant: N
Reactant: CC(C)(Cn1c(N)nc2c(Cl)nc3ccccc3c21)NS(C)(=O)=O
Agent: Br
Solvent: CO
Product: CC(C)(Cn1c(N)nc2c(N)nc3ccccc3c21)NS(C)(=O)=O
Temperature: 150 °C

Procedure:
Crude N-[2-(2-amino-4-chloro-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide hydrobromide (0.400 g) and ammonia (25 mL of a 7 N solution in methanol) were added to a high-pressure vessel, which was sealed and heated overnight in an oven at 150° C. The resulting solution was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel (eluting with 2-6% methanol in dichloromethane with 1% ammonium hydroxide added.) A portion of the product was recrystallized from acetonitrile and a small amount of methanol, isolated by filtration, and washed with diethyl ether to provide 39 mg of N-[2-(2,4-diamino-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide as brown needles, mp >230° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:11]([CH3:29])[C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH3:23])=[C:17]([CH2:24][C:25]([OH:27])=[O:26])[C:16]=3[CH:15]=[CH:14][C:13]=2[N:28]=1.[CH2:30](O)[CH3:31]>OS(O)(=O)=O>[CH2:30]([O:26][C:25](=[O:27])[CH2:24][C:17]1[C:16]2[CH:15]=[CH:14][C:13]3[N:28]=[C:10]([NH:9][C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])[N:11]([CH3:29])[C:12]=3[C:21]=2[C:20](=[O:22])[NH:19][C:18]=1[CH3:23])[CH3:31]
Reactant: Cc1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1CC(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1c(C)[nH]c(=O)c2c1ccc1nc(Nc3c(Cl)cccc3Cl)n(C)c12

Procedure:
Prepared from 2-(2,6-dichlorophenylamino)-1,7-dimethyl-9-oxo-1,8-dihydro-imidazo[4,5-h]isoquinolin-6-yl acetic acid by refluxing in ethanol and H2SO4. Mp 280-285° C. (dec); MS(CI) 459, 461 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12]CC)=[O:11])=[CH:4][C:3]=1[NH:15][C:16]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:19]=1)=[O:17].O[Li].O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[NH:15][C:16]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:19]=1)=[O:17]
Reactant: CCOC(=O)/C=C/c1ccc(Cl)c(NC(=O)c2cc(-c3ccccc3)cc3ccccc23)c1
Agent: [Li]O
Solvent: O
Product: O=C(O)/C=C/c1ccc(Cl)c(NC(=O)c2cc(-c3ccccc3)cc3ccccc23)c1

Procedure:
Compound 6c was synthesized from 5c (0.63 mmol) and LiOH.H2O (1.9 mmol) using the procedure according to the above Method E.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][C:5]2=1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:33]=[C:34]([C:36]1[CH:41]=[CH:40][C:39]([F:42])=[C:38]([F:43])[CH:37]=1)[CH3:35]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:33]=[C:34]([C:36]1[CH:41]=[CH:40][C:39]([F:42])=[C:38]([F:43])[CH:37]=1)[CH3:35])[C:6]1[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][C:5]2=1
Reactant: CN1CCc2c([nH]c3ccc(Cl)cc23)C1
Reactant: CC(=CBr)c1ccc(F)c(F)c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CC(=Cn1c2c(c3cc(Cl)ccc31)CCN(C)C2)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46 %

Procedure:
6-chloro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (79 mg, 0.35 mmol) was dissolved in DMF (6 mL). To this solution was added CuI (8 mg, 0.035 mmol), L-proline (9 mg, 0.086 mmol), K3PO4 (183 mg, 0.862 mmol). The reaction mixture was stirred for 10 min at room temperature followed by addition of 4-(1-bromoprop-1-en-2-yl)-1,2-difluorobenzene (100 mg, 0.431 mmol). The reaction mixture was heated at 80° C. overnight. Solvent was evaporated under reduced pressure, the residue was diluted with brine and extracted with ethyl acetate. Organic layer was dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to obtain 60 mg of 6-chloro-9-(2-(3,4-difluorophenyl)prop-1-enyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole. 1H NMR (DMSO) OXALATE SALT 7.80 (m, 1H), 7.60 (s, 1H), 7.50 (m, 2H), 7.25 (d, 1H), 7.15 (s, 2H), 4.10 (m, 2H), 3.30 (m, 2H), 2.95 (m, 2H), 2.78 (s, 3H), 1.82 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][OH:26].[OH-].[K+]>C1(C)C=CC=CC=1.C1OCCOCCOCCOCCOCCOC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][CH:17]=[C:16]([O:26][CH2:25][C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([Cl:21])[CH:23]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cncc(Cl)n2)CC1
Reactant: OCc1cccc(Cl)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cncc(OCc3cccc(Cl)c3)n2)CC1
Yield: 93.9 %

Procedure:
A mixture of 6′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (I-1a) (300 mg, 1.0 mmol), 3-chlorobenzyl alcohol (0.142 mL, 1.2 mmol), KOH (191 mg, 3.4 mmol) and 18-crown-6 (10.6 mg, 0.04 mmol) in toluene (6 mL) was stirred at reflux for 5.5 h and concentrated in vacuo. The residue was partitioned between H2O (30 mL) and CH2Cl2 (30 mL). The aqueous phase was separated and extracted with CH2Cl2 (2×30 mL). The combined organic extracts were dried and concentrated in vacuo. The crude product was purified by preparative TLC (5% MeOH in CH2Cl2) to afford the title compound (I-1b) (380 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCOCC>CO>[F:27][C:24]([F:25])([F:26])[C:21]1[CH:20]=[CH:19][C:18]([CH2:17][O:16][CH2:15][CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOCc2ccc(C(F)(F)F)cc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: FC(F)(F)c1ccc(COCCC2CCNCC2)cc1
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-[2-[4-(trifluoromethyl)benzyloxy]ethyl]piperidine (496 mg, 1.28 mmol) in MeOH (0.5 mL) was added 2N anhydrous HCl/ether (2.0 mL, 4.0 mmol). The reaction mixture was stirred overnight. After evaporation, the residue was dissolved in deionized water. EtOAc was used to wash the aqueous layer before the pH was altered to approx. 9-10. The aqueous layer was extracted three times with CH2Cl2 and dried over Na2SO4. After evaporation, 4-[2-[4-(trifluoromethyl)benzyloxy]ethyl]piperidine (321 mg, 87%) was obtained as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 7.56 (d, 2H, J=8.4 Hz), 7.41 (d, 2H, J=8.0 Hz), 4.51 (s, 2H), 3.50 (t, 2H, J=6.0 Hz), 3.39 (br, 1H), 3.07 (d, 2H, J=12.0 Hz), 2.59 (t, 2H, J=11.6 Hz), 1.66 (d, 2H, J=12.8 Hz), 1.54 (m, 3H), 1.20 (m, 2H).
Reaction SMILES: [NH2:1][C@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][C:22]([CH3:27])([CH3:26])[C:23](Cl)=[O:24].C(N(CC)CC)C>C(Cl)Cl>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C@H:2]([NH:1][C:23](=[O:24])[C:22]([CH3:27])([CH3:26])[CH3:21])[C:3]1=[O:20]
Reactant: CN1C(=O)[C@@H](N)N=C(c2ccccc2)c2ccccc21
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C(=O)[C@@H](NC(=O)C(C)(C)C)N=C(c2ccccc2)c2ccccc21
Reaction time: 0.17 h

Procedure:
Equimolar amounts of 3(S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, trimethylacetylchloride and triethylamine were mixed in CH2Cl2 at room temperature and stirred 10 minutes. Flash chromatography of the reaction solution on silica gel (10% Et2O in CH2Cl2) provided the title compound as a white foam after removal of the solvent: m.p. 85°-94° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[S:11][CH:12]=1.F[C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:35])[CH2:33][CH3:34])=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:26]3[CH:31]=[CH:30][C:29]([C:32](=[O:35])[CH2:33][CH3:34])=[CH:28][CH:27]=3)=[CH:15][CH:14]=2)[S:11][CH:12]=1
Reactant: COC(=O)Cc1c(-c2ccccc2Cl)csc1-c1ccc(O)cc1
Reactant: CCC(=O)c1ccc(F)cc1
Product: CCC(=O)c1ccc(Oc2ccc(-c3scc(-c4ccccc4Cl)c3CC(=O)OC)cc2)cc1

Procedure:
Methyl [4-(2-chlorophenyl)-2-(4-hydroxyphenyl)thien-3-yl]acetate was reacted as in Example 9, Step 2 with p-fluoropropiophenone (0.213 g, 1.40 mmol) to yield methyl {4-(2-chlorophenyl)-2-[4-(4-propionylphenoxy)phenyl]thien-3-yl}acetate (0.398 g). This material was reacted as in Example1, Steps 7 and 8 to yield N″-({4-(2-chlorophenyl)-2-[4-(4-propionylphenoxy)phenyl]thien-3-yl}acetyl)guanidine (0.151 g) as a white solid. mp 123-124° C.; 1H NMR (500 MHz, DMSO-d6) δ: 1.04 (t, 3H, J=7.2 Hz), 2.98 (q, 2H, J=7.2 Hz), 3.23 (s, 2H), 7.08 (d, 2H, J=8.9 Hz), 7.14 (d, 2H, J=8.7 Hz), 7.31 (m, 4H), 7.47 (d, 1H, J=8.1 Hz), 7.59 (d, 2H, J=8.7 Hz), 7.96 (d, 2H, J=8.9 Hz). MS (ES) m/z 518.10 ([M+H]+).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:14]=[C:13]2[CH2:15][CH2:16][CH2:17][CH2:18][C:12]2=[C:11]2[C:7]=1[C:8]([C:28](=[O:32])[C:29]([NH2:31])=[O:30])=[C:9]([CH2:26][CH3:27])[N:10]2[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[Li+]>O1CCCC1.CO>[NH2:31][C:29](=[O:30])[C:28]([C:8]1[C:7]2[C:11](=[C:12]3[CH2:18][CH2:17][CH2:16][CH2:15][C:13]3=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:33])=[O:2])[N:10]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]=1[CH2:26][CH3:27])=[O:32]
Reactant: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)cc3c(c2n1Cc1ccccc1)CCCC3
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cc3c(c2n1Cc1ccccc1)CCCC3
Yield: 88.2 %

Procedure:
A solution of 2-[[3-(2-amino-1,2-dioxoethyl)-1-benzyl-2-ethyl-6,7,8,9-tetrahydro-1H-benz[g]indol-4-yl]oxy]acetic acid methyl ester (150 mg, 0.334 mmol) in 3:1 tetrahydrofuran/methanol (4 mL) was treated with 1 M lithium hydroxide solution (1 mL) at room temperature for 1 h. The reaction mixture was concentrated in vacuo to one half the original volume and treated with 1 M hydrochloric acid (1 mL). The resulting suspension was diluted with water (5 mL), stirred, and the precipitate collected via vacuum filtration. This material was washed with water and dried to provide 128 mg (88%) of the title compound as a yellow solid: mp 222-225° C. 1H NMR (DMSO-d6) δ 7.72 (bs, 1H), 7.33 (m, 0.4H), 6.87 (d, J=7.3 Hz, 2H), 6.23 (s, 1H), 5.65 (s, 2H), 4.56 (s, 2H), 2.87 (m, 2H), 2.72 (m, 4H), 1.59 (m, 4H), 1.07 (t, J=7.3 Hz, 3H); MS ES+ m/e 435 (p+1); IR (CHCl3, cm−1) 3507, 3472, 3393, 2938, 1759, 1640.
Reaction SMILES: C([O:8][N:9]1[CH2:17][C:16]2[C:11](=[N:12][CH:13]=[C:14]3[N:20]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=4[F:29])[CH:19]=[CH:18][C:15]3=2)[C:10]1=[O:30])C1C=CC=CC=1.C(ON1CC2C(=NC=C3NC=CC3=2)C1)C1C=CC=CC=1.FC1C=C(F)C=CC=1CBr>>[F:29][C:23]1[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:22]=1[CH2:21][N:20]1[C:14]2[C:15](=[C:16]3[CH2:17][N:9]([OH:8])[C:10](=[O:30])[C:11]3=[N:12][CH:13]=2)[CH:18]=[CH:19]1
Reactant: O=C1c2ncc3c(ccn3Cc3ccc(F)cc3F)c2CN1OCc1ccccc1
Agent: Fc1ccc(CBr)c(F)c1
Agent: c1ccc(CON2Cc3ncc4[nH]ccc4c3C2)cc1
Product: O=C1c2ncc3c(ccn3Cc3ccc(F)cc3F)c2CN1O

Procedure:
2-Benzyloxy-6-(2,4-difluoro-benzyl)-1,6-dihydrodipyrrolo[3,2-d: 3′,4′-b]pyridin-3(2H)-one. The title compound was prepared by alkylation of 2-benzyloxy-1,6-dihydrodipyrrolo[3,2-d:3′,4′-b]pyridin-3(2H-one with 2,4-difluorobenzyl bromide in a manner similar to step (a) of example 1. 1H NMR (CD3OD) δ; 8.91 (s, 1H), 7.75 (d, 1H, J=3.0 Hz), 7.51–7.54 (m, 2H), 7.38–7.40 (m, 3H), 7.27–7.29 (m, 1H), 7.02–7.05 (m, 1H), 6.93–7.01 (m, 1H), 6.71 (d, 1H, J=3.0 Hz), 5.64 (s, 2H), 5.18 (s, 2H), 4.65 (s, 2H). LCMS (API-ES, M+H+): 406.1.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:21]1[C:22]([C:34]#[N:35])=[N:23][N:24]([CH2:31][CH2:32][CH3:33])[C:25]=1[CH2:26][CH2:27][CH2:28][CH2:29][Cl:30]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:21]1[C:22]([C:34]#[N:35])=[N:23][N:24]([CH2:31][CH2:32][CH3:33])[C:25]=1[CH2:26][CH2:27][CH2:28][CH2:29][Cl:30]
Reactant: CCCn1nc(C#N)c(Br)c1CCCCCl
Reactant: Nc1ccccc1B(O)O
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCn1nc(C#N)c(-c2ccccc2N)c1CCCCCl
Temperature: 110 °C
Reaction time: 24 h
Yield: 91.2 %

Procedure:
2-Aminophenyl boronic acid hydrochloride (9.10 mg, 26.3 mmol) and freshly ground potassium phosphate tribasic (27.8 g, 131 mmol) were added sequentially to a solution of 4-bromo-5-(4-chlorobutyl)-1-propyl-1H-pyrazole-3-carbonitrile (8.00 g, 26.3 mmol), prepared as described in Example 46, in 100 mL of toluene in a pressure tube. Nitrogen was bubbled through the resultant slurry for 15 minutes. Tris(dibenzylideneacetone)dipalladium(0) (1.36 g, 1.31 mmol), bis[(2-diphenylphosphino)phenyl]ether (851 mg, 1.58 mmol), and 4 angstrom molecular sieves were then added to the reaction mixture. The pressure tube was sealed and heated in a 110° C. oil bath. After 24 hours, the reaction mixture was cooled to ambient temperature, diluted with ethyl acetate and filtered through CELITE filter aid. The filtrate was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with additional ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated to a red oil. Purification via flash column chromatography on silica gel (eluting with 2:1 hexane:ethyl acetate) afforded 7.60 g of 4-(2-aminophenyl)-5-(4-chlorobutyl)-1-propyl-1H-pyrazole-3-carbonitrile as a red oil.
Reaction SMILES: [CH3:1][N:2]([CH2:17][CH:18]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=1)[CH2:19][CH2:20]S(C)(=O)=O)[C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1.I.[NH:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:35]1[C:43]([CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)=[O:44]>>[CH3:1][N:2]([CH2:17][CH:18]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=1)[CH2:19][CH2:20][N:48]1[CH2:49][CH2:50][CH:45]([C:43]([C:35]2[NH:34][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[N:36]=2)=[O:44])[CH2:46][CH2:47]1)[C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1
Reactant: O=C(c1nc2ccccc2[nH]1)C1CCNCC1
Reactant: COc1cc(C(=O)N(C)CC(CCS(C)(=O)=O)c2ccc(C)c(C)c2)cc(OC)c1OC
Agent: I
Product: COc1cc(C(=O)N(C)CC(CCN2CCC(C(=O)c3nc4ccccc4[nH]3)CC2)c2ccc(C)c(C)c2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 1.7 using N-methyl-N-(2-(3,4-dimethylphenyl)-4-methanesulfonylbutyl)-3,4,5-trimethoxybenzamide and 4-(1H-benzimidazole-2-carbonyl)piperidine hydriodic acid salt to give the title compound.
Reaction SMILES: Cl.C([N:4]1[CH2:13][CH2:12][C@@:11]2(C3C=CC=C(OC)C=3)[C@@H:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)[CH2:5]1)C.C[N:24](C)[C:25](=O)[C:26](=NNC1C=CC=CC=1)[C:27](=O)C.CC(O[Na])=O>[Zn].C(O)(=O)C>[CH3:27][C:26]1[C:8]2[CH2:7][CH:6]3[CH:11]([CH2:12][CH2:13][NH:4][CH2:5]3)[CH2:10][C:9]=2[NH:24][CH:25]=1
Reactant: CC(=O)C(=NNc1ccccc1)C(=O)N(C)C
Reactant: CCN1CC[C@]2(c3cccc(OC)c3)CC(=O)CC[C@H]2C1
Agent: CC(=O)O[Na]
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1c[nH]c2c1CC1CNCCC1C2
Yield: 84.8 %

Procedure:
1.0 g (3.1 mmol) of (±)-trans-2-ethyl-4a-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline hydrochloride, 2.33 g (10 mmol) of N, N-dimethyl-2-phenylhydrazono-3-oxobutyramide, 0.82 g (1 0 mmol) of CH3COONa, 2.6 g (40 mmol) of zinc dust and 5 ml of glacial acetic acid were treated as described in example 1. The residue was purified by chromatography on silica gel (EtOAc/MeOH 0%→30%) yielding 0.5 g of product which was crystallized from Et2O yielding 0.5 g of the title compound. M.p.=151°-153° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.I[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+].C(=O)([O-])O.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[NH:1]([C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Ic1ccccc1
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: O=C(Nc1cccc(Oc2ccc3nc(Nc4ccccc4)cn3n2)c1)c1cccc(C(F)(F)F)c1
Temperature: 80 °C
Yield: 16 %

Procedure:
A mixture of N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (100 mg, 0.242 mmol), iodobenzene (32 μl, 0.290 mmol), tris(dibenzylideneacetone)dipalladium (0) (11 mg, 24.2 μmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (23 mg, 48.4 μmol), sodium tert-butoxide (34 mg, 0.362 mmol) and toluene (2 mL) was stirred under an argon atmosphere with heating at 80° C. for 5 hr. After the reaction mixture was allowed to cool to room temperature, saturated aqueous sodium hydrogencarbonate solution was added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→50/50) to give the title compound (19 mg, 16%) as a pale-green powder.