Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=C[NH+]=CC=1.Br[Br-]Br.[CH2:10]([N:17]1[C:29]2[CH2:28][CH2:27][CH2:26][C:25](=[O:30])[C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([F:31])[CH:22]=2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Br-].[Li+].C(=O)([O-])[O-].[Li+].[Li+]>C1COCC1.CN(C=O)C>[CH2:10]([N:17]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:30])[C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([F:31])[CH:22]=2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CCCc2c1c1cc(F)ccc1n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Oc1cccc2c1c1cc(F)ccc1n2Cc1ccccc1
Temperature: 75 °C
Reaction time: 6.5 h
Yield: 59.1 %

Procedure:
Pyridinium bromide perbromide (0.4620 g, 0.0014 mol) is added to a mixture of 9-benzyl-6-fluoro-1,2,3,9-tetrahydro-4H-carbazol-4-one (0.3271 g, 0.0011 mol) in THF (3.4 mL) and DMF (2.4 mL) and the mixture is heated to 75° C. After stirring for 6.5 h, the mixture is stored in the freezer overnight. Heating is resumed for an additional 2.5 h, at which time THF is removed under reduced pressure and the residue is partitioned between dichloromethane and brine. The combined organic layers are washed with dilute sodium thiosulfate/brine and the aqueous layer is backwashed with dichloromethane. The combined organic layers are dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue is heated to 120° C. in DMF (5 mL) with lithium bromide (0.2348 g, 0.0027 mol) and lithium carbonate (0.1813 g, 0.0025 mol). After 2 h, DMF is removed under high vacuum and the mixture is partitioned between dichloromethane and water. The combined organic layers are washed with water and the aqueous layer is backwashed with dichloromethane. The combined organic layers are dried over sodium sulfate and concentrated to an oil. The oil is chromatographed on silica gel (100 mL) using dichloromethane/hexane (30/70 and 50/50) to give 0.1893 g (58%) of the title compound. An aliquot is precipitated from hexane/ ether; MS (ESI+) for C19H14FNO m/z 292.2 (M+H)+; IR (drift) 1483, 1466, 1451, 1337, 1304, 1174, 1157, 1138, 884, 859, 794, 777, 745, 713, 700 cm−1; 1H NMR (CDCl3) δ5.34, 5.47, 6.56, 6.95, 7.13, 7.20-7.30, 8.01. Anal. Calcd for C19H14FNO: C, 78.33; H, 4.84; N, 4.81. Found: C, 78.17; H, 4.83; N, 4.78.
Reaction SMILES: [CH3:1][Mg]I.CON(C)[C:7]([C:9]1[S:10][C:11]([C:37]2[CH:42]=[CH:41][C:40]([S:43][CH3:44])=[CH:39][CH:38]=2)=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:21]=[C:22]([C:30]([CH3:36])([S:32]([CH3:35])(=[O:34])=[O:33])[CH3:31])[CH:23]=[C:24]4[C:29]=3[N:28]=[CH:27][CH:26]=[CH:25]4)[CH:15]=2)[N:13]=1)=[O:8]>>[CH3:31][C:30]([C:22]1[CH:23]=[C:24]2[C:29](=[C:20]([C:16]3[CH:15]=[C:14]([C:12]4[N:13]=[C:9]([C:7](=[O:8])[CH3:1])[S:10][C:11]=4[C:37]4[CH:38]=[CH:39][C:40]([S:43][CH3:44])=[CH:41][CH:42]=4)[CH:19]=[CH:18][CH:17]=3)[CH:21]=1)[N:28]=[CH:27][CH:26]=[CH:25]2)([S:32]([CH3:35])(=[O:34])=[O:33])[CH3:36]
Reactant: C[Mg]I
Reactant: CON(C)C(=O)c1nc(-c2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)c(-c2ccc(SC)cc2)s1
Product: CSc1ccc(-c2sc(C(C)=O)nc2-c2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)cc1

Procedure:
Prepared according to the general procedure Cer-1 using methylmagnesium iodide and amide from step 2.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:20]2[C:19](=[O:25])[CH2:18][C@@:17]2([CH3:26])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:16])[CH2:13][O:14][CH3:15])[CH2:3]1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>N1C=CC=CC=1>[CH3:15][O:14][CH2:13][C:12](=[O:16])[C@@H:11]1[C@:17]2([CH3:26])[C@H:8]([C@H:7]3[C@H:20]([C:19](=[O:25])[CH2:18]2)[C@:21]2([CH3:24])[C@H:4]([CH2:3][C@H:2]([O:1][S:33]([C:30]4[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=4)(=[O:35])=[O:34])[CH2:23][CH2:22]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Solvent: c1ccncc1
Product: COCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OS(=O)(=O)c5ccc(C)cc5)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Yield: 72.5 %

Procedure:
3α-Hydroxy-21-methoxy-5α-pregnane-11,20-dione (1.5 g.) in dry pyridine (7.5 ml.) was treated with toluene p-sulphonyl chloride (1.5 g.) at room temperature overnight. The reaction mixture was then partitioned between 2N-hydrochloric acid and chloroform, washed with water, dried (Na2SO4) and evaporated to give 21-methoxy-3α-(p-toluene sulphonyloxy)-5α-pregnane-11,20-dione (1.55 g.) as a foam.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][CH2:18][OH:19])[CH2:12][CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[N+]([C:30]1C=CC(N2CCC(=O)CC2)=C(C=1)C#N)([O-])=O.COCCN>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][CH2:18][O:19][CH3:30])[CH2:12][CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N1CCC(=O)CC1
Reactant: CC(C)(C)OC(=O)N(CCO)C1CCN(c2ccc(N)cc2C#N)CC1
Agent: COCCN
Product: COCCN(C(=O)OC(C)(C)C)C1CCN(c2ccc(N)cc2C#N)CC1

Procedure:
By the reaction and treatment in the same manner as in Starting Material Synthesis Example 85(2), (3) and (4) using 5-nitro-2-(4-oxopiperidino)benzonitrile and 2-methoxyethylamine, the title compound as obtained.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][S:16]([C:19]2[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[CH:21][C:20]=2[O:27][CH3:28])(=[O:18])=[O:17])=[C:9]([O:29][CH2:30][O:31][CH3:32])[CH:8]=1)(=O)=O.C([O-])(=O)C.[K+].Br[C:41]1[CH:46]=[C:45]([F:47])[C:44]([F:48])=[C:43]([F:49])[CH:42]=1.[PH2](=O)[O-].[K+]>O.C(OCC)(=O)C.O1CCOCC1>[C:25]([C:23]1[CH:22]=[CH:21][C:20]([O:27][CH3:28])=[C:19]([S:16]([NH:15][CH2:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([C:41]3[CH:46]=[C:45]([F:47])[C:44]([F:48])=[C:43]([F:49])[CH:42]=3)=[CH:8][C:9]=2[O:29][CH2:30][O:31][CH3:32])(=[O:18])=[O:17])[CH:24]=1)#[N:26]
Reactant: Fc1cc(Br)cc(F)c1F
Reactant: COCOc1cc(OS(=O)(=O)C(F)(F)F)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1OC
Agent: CC(=O)[O-]
Agent: O=[PH2][O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COCOc1cc(-c2cc(F)c(F)c(F)c2)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1OC
Temperature: 80 °C
Reaction time: 15 h
Yield: 104.6 %

Procedure:
A mixture of 10.0 g of 4-[2-(5-cyano-2-methoxy-benzenesulfonylamino)ethyl]-3-methoxymethoxyphenyl trifluoromethanesulfonate, 5.33 g of bis(pinacoloto)diboron, 467 mg of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride dichloromethane complex, 317 mg of 1,1′-bis-(diphenylphosphino)ferrocenepalladium(II), 5.61 g of potassium acetate, and 113 mL of 1,4-dioxane was stirred under an argon atmosphere at 80° C. for 15 hours. To the reaction mixture were added 4.02 g of 1-bromo-3,4,5-trifluorobenzene, 467 mg of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride dichloromethane complex, 12.14 g of potassium phosphinate, and 40 mL of 1,4-dioxane. The mixture was stirred under argon atmosphere at 80° C. for 24 hours, and ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on aminopropylated silica gel (eluent: ethyl acetate-hexane) to give 10.09 g of 5-cyano-2-methoxy-N-[2-(3′,4′,5′-trifluoro-3-methoxymethoxybiphenyl-4-yl)ethyl]-benzenesulfonamide.
Reaction SMILES: [I:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([O:16][CH3:17])[C:7]([N+:13]([O-])=O)=[CH:8][CH:9]=2)[O:4][C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl[Sn]Cl>C(OCC)(=O)C>[NH2:13][C:7]1[C:6]([O:16][CH3:17])=[C:5]2[C:10]([C:11](=[O:12])[C:2]([I:1])=[C:3]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:4]2)=[CH:9][CH:8]=1
Reactant: COc1c([N+](=O)[O-])ccc2c(=O)c(I)c(-c3ccccc3)oc12
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Product: COc1c(N)ccc2c(=O)c(I)c(-c3ccccc3)oc12
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 91.1 %

Procedure:
To a suspension of 3-iodo-8-methoxy-7-nitro-2-phenyl-chromen-4-one (903 mg, 2.1 mmol) in ethyl acetate (7 mL) and IMS (7 mL) was added SnCl2 (2.37 g, 10.5 mmol). The reaction mixture was stirred at 80° C. for 1.5 hours before cooling to cool to RT. The resultant mixture was partitioned between ethyl acetate and water and the phases separated. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried (NaSO4), filtered, and the solvent removed in vacuo. The resulting residue was subjected to flash chromatography (SiO2, gradient 40-50% ethyl acetate in cyclohexane) to give the title compound as a yellow solid (752 mg, 91%). LCMS (Method G): RT=3.35 min, [M+H]+=394.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13](S(C)(=O)=O)=[N:14][CH:15]=2)[N:10]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][OH:30])[CH:23]=2)[C:9]1=[O:31].COC1C=CC(C[NH2:39])=CC=1>>[NH2:39][C:13]1[N:12]=[C:11]2[N:10]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][OH:30])[CH:23]=3)[C:9](=[O:31])[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Br:1])[CH2:17][C:16]2=[CH:15][N:14]=1
Reactant: CS(=O)(=O)c1ncc2c(n1)N(c1cccc(CCO)c1)C(=O)N(c1ccccc1Br)C2
Reactant: COc1ccc(CN)cc1
Product: Nc1ncc2c(n1)N(c1cccc(CCO)c1)C(=O)N(c1ccccc1Br)C2
Temperature: 100 °C
Yield: 40 %

Procedure:
A mixture of 300 mg (0.6 mmol) of 3-(2-bromophenyl)-7-methanesulfonyl -3,4-dihydro-1-[3-(2-hydroxyethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one and 1.5 ml of 4-methoxybenzylamine was heated at 100° C. for 1 hour. The mixture was cooled and partitioned between 30 ml of dichloromethane and 30 ml of 2M aqueous hydrochloric acid. The organic phase was dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in 10 ml of trifluoroacetic acid and then heated at reflux for 3 hours. The mixture was cooled and evaporated and the residue was partitioned between 25 ml of ethyl acetate and 25 ml of saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate, filtered and evaporated and the residue was subjected to column chromatography on silica gel using ethyl acetate for the elution. Product-containing fractions were combined and evaporated to give 105 mg (40%) of 7-amino-3-(2-bromophenyl)-3,4-dihydro-1-[3-(2-hydroxyethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 154° C.
Reaction SMILES: FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][C:15]([CH3:17])=[O:16].[Br:22]Br.O>C(Cl)Cl>[CH2:20]([O:19][C:13](=[O:18])[CH:14]([Br:22])[C:15](=[O:16])[CH3:17])[CH3:21]
Reactant: CCOC(=O)CC(C)=O
Reactant: BrBr
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(Br)C(C)=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
At −5° C. trimethylsilyl trifluoromethanesulfonate (36.9 mmol) is added dropwise to a solution of ethyl acetoacetate (30.7 mmol) and TEA (36.9 mmol) in DCM (50 mL). The solution is stirred for 90 min at 0° C. and treated over 30 min with a solution of bromine (30.7 mmol) in DCM (20 mL). After 60 min water (100 mL) is added, the layers are separated and the aq. layer is extracted three times with water (100 mL each). The organic layer is dried over MgSO4 and concentrated under reduced pressure to give the desired product which is used without further purification. 1H-NMR (CDCl3): δ=1.34 (t, J=7.16 Hz, 3H); 2.46 (s, 3H); 4.31 (q, J=7.20 Hz, 2H); 4.77 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:3]=1.[CH2:11]=[O:12].C(N(CC)CC)C>CC(C)=O>[Br:1][C:2]1[N:6]([CH2:11][OH:12])[N:5]=[C:4]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:3]=1
Reactant: C=O
Reactant: CC(C)(C)c1n[nH]c(Br)n1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1nc(Br)n(CO)n1
Temperature: 130 °C
Reaction time: 5 h
Yield: 72.8 %

Procedure:
The mixture of 3.45 g of 5-bromo-3-t-butyl-1H-1,2,4-triazole, 0.61 g of paraformaldehyde and 0.17 g of triethylamine was stirred at 130 ° C. for 5 hours. After the reaction mixture was cooled to room temperature, acetone was added. The mixture was filtered. Hexane was added to the residue and filtered. The filtrate was concentrated under reduced pressure to obtain 2.88 g of 5-bromo-3-t-butyl-1H-1,2,4-triazole1-ylmethanol.
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH2:7])=[CH:5][S:4][CH:3]=1.[C:8](Cl)(=[O:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].Cl>N1C=CC=CC=1>[C:8]([NH:1][C:2]1[C:6]([NH:7][C:8](=[O:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:5][S:4][CH:3]=1)(=[O:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: Nc1cscc1N
Reactant: CCCCCCCCCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCC(=O)Nc1cscc1NC(=O)CCCCCCCCC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3,4-Diaminothiophene (2.0 g, 17 mmol) was dissolved in pyridine and the solution was added dropwise to a stirred solution of 6.5 g (34 mmol) of decanoyl chloride (boiling point 125° C. at 45 mbar) via a syringe. It was stirred overnight. The reaction mixture was poured into ice water mixed with concentrated hydrochloric acid and extracted with chloroform. The organic layers were washed with water, 2% strength NaOH and again with water and then dried over MgSO4 which was mixed with active carbon to remove the colored impurities. After evaporating the solvent, a solid was obtained which was recrystallized from a toluene-hexane mixture. The solid had a melting point of 99-100° C. The yield was 6.7 g (90% of theory).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[N:18]1([C:4]2[CH:5]=[C:6]([S:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)(=[O:10])=[O:9])[CH:7]=[C:2]([C:26]3[CH:27]=[CH:28][C:23]([CH3:32])=[CH:24][CH:25]=3)[N:3]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(N3CCCC3)c2)cc1
Reactant: Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cc(S(=O)(=O)c3ccc(N)cc3)cc(N3CCCC3)n2)cc1
Yield: 40.7 %

Procedure:
A mixture of 191 mg (0.5 mmole) 4-(2-bromo-6-pyrrolidine-1-yl-pyridine-4-sulfonyl)-phenylamine, 84 mg (0.55 mmole) 4-tolylboronic acid, 18 mg bis(triphenylphosphine)-palladium(II)-chloride is refluxed for 2.5 hours in 7 ml toluene and 2 ml 2N aqueous potassium carbonate. The solvents are removed in vacuo. Flash chromatography (silicagel, ethyl acetate/hexane 1/1) of the residue yields 80 mg (40%) pure 4-(2-pyrrolidine-1-yl-6-p-tolyl-pyridine-4-sulfonyl)-phenylamine as a pale yellow solid mp.: 250-251° C.
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:20])[N:11]([CH3:19])[C:12](=[O:18])[N:13]([CH3:17])[C:14]=1[CH2:15]Br)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:22][O:23][C:24](=[O:28])[CH2:25][CH2:26][NH2:27].C(N(CC)CC)C>CCO.C(Cl)Cl>[CH3:17][N:13]1[C:14]2=[CH:15][N:27]([CH2:26][CH2:25][C:24]([O:23][CH3:22])=[O:28])[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:9]2[C:10](=[O:20])[N:11]([CH3:19])[C:12]1=[O:18]
Reactant: COC(=O)CCN
Reactant: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCn1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C

Procedure:
5-Benzoyl-6-(bromomethyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (Intermediate C) (3 g, 8.90 mmol), beta alanine methyl ester hydrochloride (1.242 g, 8.90 mmol) and triethylamine (2.480 mL, 17.80 mmol) in EtOH (63.6 mL) was heated to 100° C. for 90 min using microwave radiation. The reaction mixture was diluted with of DCM (80 ml) and washed with water and 0.1M HCl. The organic portion was dried by passing through a phase separating cartridge and concentrated in vacuo to yield the title compound as a pale yellow oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([NH2:16])=[N:8]1)[CH3:2].[N+:19]([O-])(O)=O.N.Cl>S(=O)(=O)(O)O.[Fe].C(Cl)(Cl)Cl.O>[CH2:17]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH2:19])=[CH:13][CH:14]=2)[C:9]([NH2:16])=[N:8]1)[CH3:18]
Reactant: O=[N+]([O-])O
Reactant: CCN(CC)CCCn1nc(N)c2ccccc21
Agent: [Fe]
Agent: Cl
Agent: N
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCN(CC)CCCn1nc(N)c2cc(N)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
In 2.58 ml of sulfuric acid was dissolved 1.5 g of 1-(3-diethylaminopropyl)-3-aminoindazole, and to the solution were added dropwise 0.41 ml of nitric acid (d-1.42) and 0.41 ml of sulfuric acid (sp.gr. 1.84) under cooling with ice. The solution was stirred for 2 hours at 5°-10° C. and then added to 12.1 ml of ice and water. The pH of the solution was adjusted to at least 11 with aqueous ammonia solution and the solution was extracted with chloroform. The chloroform layer was dried with anhydrous sodium sulfate and chloroform was removed under reduced pressure. In 50 ml of anhydrous benzene was dissolved the residue obtained. To the solution were added 10 g of iron powder and 2 ml of hydrochloric acid, and the solution was stirred for 30 minutes at 80° C. The solution was further added with 0.5 ml of water and stirred for 10 hours at 80° C. After cooling the solution, the solution was filtered and the benzene layer obtained as the filtrate was extracted three times with 20 ml of lN-hydrochloric acid. The pH of the hydrochloric acid layer was adjusted to at least 11 with potassium carbonate, and the alkali layer was extracted with chloroform. The chloroform layer was dried with anhydrous sodium sulfate, and chloroform was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography (alumina: 100 g) using chloroform as the developing solvent to give 0.65 g of 1-(3-diethylaminopropyl)-3,5-diaminoindazole having the following analytical values in a yield of 41%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.C(N(CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>CO>[Br:20][C:16]1[N:15]=[C:14]([C:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH:10]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(Br)n2)CC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc(Br)n2)CC1
Temperature: 128 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
As shown in FIG. 7—step ii, compound 1031 (2.0 g) was mixed with TFA (25 mL) in a sealed tube and heated at 128° C. for 2 days. Removal of the TFA gave a residue, which was dissolved in methanol (30 mL) and treated with triethylamine (2 mL) and di-tert-butyl dicarbonate (1.4 mL). After 1 hour, the volatiles were removed in vacuo and water (100 mL) was added. Extraction with dichloromethane (3×), concentration, and purification by chromatography (SiO2, 20% ethyl acetate/hexane) gave 6-bromo-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid, tert-butyl ester (compound 1032) (0.96 g).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:19](O)=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC1C(O)=C(F)C(F)=C(F)C=1F.Cl.C(N=C=NCCCN(C)C)C.Cl.[NH2:51][NH2:52]>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:19]([NH:51][NH2:52])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@@H](C(=O)O)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Reactant: NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)NN)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A solution of 20 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvaleric acid in 200 ml of dimethylformamide was cooled to 0° C. under nitrogen and treated with 11.8 g of pentafluorophenol and 12.3 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. The mixture was stirred for 2.5 hours at 0° C. and then treated with 19.8 g of hydrazine hydrochloride and 33 ml of triethylamine. The mixture was left to warm to room temperature and was then stirred overnight. Evaporation gave a residue which was dissolved in ethyl acetate and washed with 2M aqueous hydrogen chloride, 5% aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. Evaporation gave a solid which was washed with ether/hexane (1:1) and dried to give 12.1 g of of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvalerohydrazide in the form of a white solid.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[C:20](Br)[CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[OH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[C:20]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[CH2:24][OH:23])[CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: OCc1ccccc1B(O)O
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(Br)cc2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(-c3ccccc3CO)cc2s1
Temperature: 80 °C
Reaction time: 14 h

Procedure:
100 mg (0.25 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 11A) and 37.8 mg (0.25 mmol) of 2-(hydroxymethyl)phenylboronic acid are introduced into 1 ml of DMF. Addition of 0.37 ml of 2 M sodium carbonate solution and 10.2 mg (0.01 mmol) of PdCl2(dppf) is followed by heating to 80° C. After 14 h, the reaction mixture is filtered through kieselguhr and purified by separation twice by preparative HPLC. The product fractions are concentrated and, after addition of a 5:1 mixture of methanol and 4N hydrogen chloride in dioxane, again concentrated. Drying under high vacuum results in 27 mg (24.4% of theory) of the title compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([CH:8](P(=O)(OCC)OCC)[CH2:9][CH3:10])=[O:7])[CH3:4].COC(=O)/C=[CH:23]/[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[CH:26][CH:25]=1.C(O)(=O)C>O1CCCC1>[CH2:3]([O:5][C:6](=[O:7])/[C:8](/[CH2:9][CH3:10])=[CH:23]/[C:24]1[CH:25]=[CH:26][C:27]([CH2:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[CH:28][CH:29]=1)[CH3:4]
Reactant: COC(=O)/C=C/c1ccc(Cc2cccnc2)cc1
Reactant: CCOC(=O)C(CC)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)/C(=C/c1ccc(Cc2cccnc2)cc1)CC
Reaction time: 0.25 h
Yield: 113.6 %

Procedure:
To a suspension of 46 mg of sodium hydride(content 63%) in 3 ml of tetrahydrofuran was added dropwise 0.33 g of diethyl 1-ethoxycarbonylpropylphosphonate at room temperature, and the mixture was stirred at that temperature for 15 minutes. To it was added a solution of 206 mg of the aldehyde (prepared as described in Reference Example 1) in one ml, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was acidified with acetic acid, and concentrated under reduced pressure. To the residue was added a saturated aqueous solution of sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (2:1) as eluent to give 273 mg of the title compound having the following physical characteristics: