Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)=[C:12]([C:19]1[CH:30]=[CH:29][C:22]([O:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C1C=CC=CC=1.C(Cl)(=O)C.C(OCC)(=O)C>C1(C)C=CC=CC=1.[Zn]>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C:11](=[C:12]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH2:24][CH2:25][N:26]([CH3:27])[CH3:28])=[CH:29][CH:30]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH2:9][OH:8])=[CH:32][CH:33]=1
Reactant: CN(C)CCOc1ccc(C(=C(CCOCc2ccccc2)c2ccc(Cl)cc2)c2ccccc2)cc1
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)Cl
Product: CN(C)CCOc1ccc(C(=C(CCO)c2ccc(Cl)cc2)c2ccccc2)cc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
(2-{4-[4-Benzyloxy-2-(4-chlorophenyl)-1-phenylbut-1-enyl]phenoxy}ethyl)dimethylamine (1.1 g, 2.1 mmol) is dissolved in toluene, Zn powder (0.4 g, 6.1 mmol) and acetyl chloride (0.6 g, 7.6 mmol) are added and the mixture is stirred at 40° C. for 3 h. Additional Zn (0.5 g) and acetyl chloride (0.6 g) are added and stirring is continued for another 5 h. Ethyl acetate is added and the precipitate is filtered off. The solvents are evaporated and the residue is dissolved in methanol. The acetate ester of the product is hydrolyzed by making the mixture alkaline with 48% aqueous sodium hydroxide and stirring the mixture at room temperature for 2 h. Methanol is evaporated, the residue is dissolved in toluene and washed with water. Toluene is evaporated and the isomers of the product are separated by flash chromatography. The yield of the Z-isomer is 0.25 g and of the E-isomer 0.15 g.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=O)=[C:9]3[N:8]=[C:7]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[CH:6]=2)[CH2:3][CH2:2]1.[NH:25]1[CH2:31][C:29](=[O:30])[NH:28][C:26]1=[O:27].N1CCCCC1>CCO>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:31]4\[NH:25][C:26](=[O:27])[NH:28][C:29]\4=[O:30])=[C:9]3[N:8]=[C:7]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=3)[CH:6]=2)[CH2:2][CH2:3]1
Reactant: O=C1CNC(=O)N1
Reactant: N#Cc1ccc(Nc2cc(NC3CC3)n3ncc(C=O)c3n2)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: N#Cc1ccc(Nc2cc(NC3CC3)n3ncc(/C=C4\NC(=O)NC4=O)c3n2)cc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 79.1 %

Procedure:
4-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-ylamino)benzonitrile (75 mg, 0.24 mmol) was suspended in EtOH (2.4 mL). Hydantoin (36 mg, 0.35 mmol) and piperidine (36 μL, 0.35 mmol) were added and the reaction was heated to 80° C. After 15 h, the solution was filtered while warm and the filter cake was washed with warm EtOH (3 mL) to give (Z)-4-(7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-ylamino)benzonitrile (76 mg, 80%) as a bright yellow solid. LCMS (ES): >90% pure, m/z 401 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][S:13][CH2:12]2)=[C:4](Cl)[N:3]=1.C(O)CCC.[F:22][C:23]([F:33])([F:32])[O:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][S:13][CH2:12]2)=[C:4]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][C:23]([F:22])([F:32])[F:33])=[CH:26][CH:27]=2)[N:3]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: Clc1nc(Cl)c2ncn(C3CCSC3)c2n1
Solvent: CCCCO
Solvent: CC(C)O
Product: FC(F)(F)Oc1ccc(Nc2nc(Cl)nc3c2ncn3C2CCSC2)cc1
Reaction time: 20 h

Procedure:
The operation is carried out as in Stage 2 of Example 5 starting from 160 mg of the product obtained in Stage 1 of Example 5, 3 ml of butanol and using 0.081 ml of 4-(trifluoromethoxy)-benzenamine in place of the benzylamine and the reaction medium is taken to a temperature of approximately 80 to 85° C. for approximately 20 hours, left to return to ambient temperature, diluted with 3 ml of isopropanol, placed for approximately one hour at a temperature of approximately 0° C., followed by separating, washing with 5 ml of isopropanol and drying under vacuum at a temperature of approximately 50° C. After purification on silica eluting with methylene chloride/ ethyl acetate in a proportion of 90/10, 203 mg of expected product is obtained in the form of white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][S:11](Cl)(=[O:13])=[O:12].Cl>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:11]([CH3:10])(=[O:13])=[O:12])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1Cl
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(Br)cnc1Cl
Reaction time: 8 h

Procedure:
5-Bromo-2-chloro-3-pyridinamine [commercially available] (10 g, 48.2 mmol) was dissolved in pyridine (75 ml) and methanesulfonyl chloride (7.46 ml, 96 mmol) added, and the mixture stirred overnight. Further methanesulfonyl chloride (2.1 ml) was added and the reaction stirred at room temperature for 5 h. A further portion of methanesulfonyl chloride (2.1 ml) was added and the mixture stirred at room temperature overnight. The pH was adjusted to ˜pH6 by the addition of 2M hydrochloric acid. The mixture was then extracted with dichloromethane (2×150 ml) the combined organic layers were dried using a hydrophobic frit and the solvent removed in vacuo. The residue was suspended in methanol (200 ml) and 2M sodium hydroxide (50 ml) added. The mixture was stirred for 1 h and then the solvent removed in vacuo. The residue was dissolved in water (250 ml) and extracted with dichloromethane (150 ml). The aqueous layer was then acidified and the resulting precipitate collected by filtration. The solid was air dried overnight to give the title compound as an off white solid (13.45 g).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[CH:11]=[O:12].C([O-])([O-])=O.[Na+].[Na+].[CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O)=[O:20]>COC(OC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[CH:11]=[O:12])=[O:20]
Reactant: O=Cc1ccccc1B(O)O
Reactant: O=Cc1c(Br)ccc2c1OCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COC(C)OC
Agent: O=C([O-])[O-]
Product: O=Cc1ccccc1-c1ccc2c(c1C=O)OCO2

Procedure:
To a solution of 5-bromo-1,3-benzodioxole-4-carbaldehyde (0.458 g, 2.00 mmol) in dry dimethoxy-ethane were added Pd(PPh3)4 (5 mol %, 0.10 mmol), 2.5 ml 2M Na2CO3 and 2-formylphenylboronic acid (0.450 g, 3.00 mmol) under argon. The reaction mixture was heated under reflux until the starting material was consumed (monitored by TLC). Then the mixture was poured onto ice-water (30 ml) and the aqueous phase was extracted with dichloromethane (3×30 ml). The combined organic phases were dried over anhydrous MgSO4. The solvent was evaporated in vacuo and the crude product was purified by column chromatography with a mixture of hexane:ethyl acetate (9:1) as the eluent.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[F:19][C:20]1[CH:21]=[C:22]([N:26]=[C:27]=[O:28])[CH:23]=[CH:24][CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([NH:26][C:27]([NH:1][C:2]2[CH:18]=[CH:17][CH:16]=[C:4]([O:5][C:6]3[CH:11]=[CH:10][N:9]=[C:8]4[NH:12][C:13](=[O:15])[NH:14][C:7]=34)[CH:3]=2)=[O:28])[CH:23]=[CH:24][CH:25]=1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Reactant: O=C=Nc1cccc(F)c1
Product: O=C(Nc1cccc(F)c1)Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Yield: 16 %

Procedure:
Method G was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 3-fluoro-phenylisocyanate to afford the title compound (10 mg, 16%). 1H-NMR (DMSO), δ (ppm), J (Hz): 6.40 (d, 1H, HPyr, J=5.9 Hz), 6.74-6.79 (m, 1H, Harom2′), 7.21 (d, 1H, Harom4 or 6, J=8.05 Hz), 7.27 (d, 1H, Harom6 or 4), 7.30-7.46 (m, 5H, Harom4′, Harom5′, Harom6′, Harom2, Harom 5), 7.79 (d, 1H, HPyr), 9.04 (s, 2H, NHurea), 11.17 (s, 1H, NHim), 11.37 (s, 1H, NHim); MS-LC, Rf=6.84 min, (C19H14FN5O3), m/z: 380.1 [M++H], 100.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>CN(C=O)C.O.C(Cl)Cl>[CH2:20]([O:12][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([OH:13])[C:2]=1[Br:1])[C:6]([O:8][CH3:9])=[O:7])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(O)c(Br)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(O)c(Br)c(OCc2ccccc2)c1
Reaction time: 8 h
Yield: 52 %

Procedure:
To a mixture of methyl 4-bromo-3,5-dihydroxybenzoate (18.8 g, 76 mmol) and potassium carbonate (5.26 g, 38.1 mmol) in DMF (190 mL) was added benzyl bromide (3.17 mL, 26.6 mmol). The mixture was stirred overnight, diluted with 200 mL water and acidified to pH 1 by slow addition of concentrated hydrochloric acid. The solution was extracted with 1:1 ethyl acetate/ether (6×) and the combined extracts were washed with water (8×), saturated sodium bicarbonate, brine, then dried over magnesium sulfate and concentrated to provide an orange solid. The solid was suspended in DCM (200 mL) and stirred overnight. The solid (primarily unreacted 4-bromo-3,5-dihydroxybenzoate) was removed by filtration and the filtrate was concentrated to provide an orange oil which was purified by column chromatography (80 g silica gel, 2:1 DCM in heptane elution, followed by DCM elution) to provide methyl 3-(benzyloxy)-4-bromo-5-hydroxybenzoate (4.66 g). MS (M+1)=337.0. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.32-7.57 (m, 6H), 7.26 (d, J=1.52 Hz, 1H), 5.77 (s, 1H), 5.22 (s, 2H), 3.93 (s, 3H) as well as the di-benzylated methyl 3,5-bis(benzyloxy)-4-bromobenzoate (1.8 g).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[NH2:15][C:16]1[C:25]([N+:26]([O-:28])=[O:27])=[C:24]2[C:19]([C:20]([CH3:32])([CH3:31])[C:21](=[O:30])[NH:22][C:23]2=[O:29])=[CH:18][CH:17]=1.O[CH2:34][CH2:35][CH2:36][N:37]([CH2:45][CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[C:49]([O:55][CH3:56])[CH:48]=1)[C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[NH2:15][C:16]1[C:25]([N+:26]([O-:28])=[O:27])=[C:24]2[C:19]([C:20]([CH3:32])([CH3:31])[C:21](=[O:30])[N:22]([CH2:34][CH2:35][CH2:36][N:37]([CH2:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[C:49]([O:55][CH3:56])[CH:48]=3)[C:38](=[O:44])[O:39][C:40]([CH3:42])([CH3:43])[CH3:41])[C:23]2=[O:29])=[CH:18][CH:17]=1
Reactant: CC1(C)C(=O)NC(=O)c2c1ccc(N)c2[N+](=O)[O-]
Reactant: COc1ccc(CCN(CCCO)C(=O)OC(C)(C)C)cc1OC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CCN(CCCN2C(=O)c3c(ccc(N)c3[N+](=O)[O-])C(C)(C)C2=O)C(=O)OC(C)(C)C)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
DIAD (1.92 mL, 9.75 mmol) was slowly added to an ice-cold solution of 7-amino-4,4-dimethyl-8-nitroisoquinoline-1,3(2H,4H)-dione (2.03 g, 8.14 mmol; prepared according to the method described in DE 3410168), tert-butyl [3-hydroxypropyl][2-(3,4-dimethoxyphenyl)ethyl]carbamate (3.31 g, 9.78 mmol), and PPh3 (2.56 g, 9.76 mmol) in THF (40 mL). The reaction mixture was allowed to warm to room temperature and was stirred at this temperature for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (40-63μ silica gel, hexane:EtOAc 1:1) to give the title compound (4.29 g, 92% yield).
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH2:9])[N:5]=[C:4]([N:10]([CH2:14][CH:15]=[CH2:16])[CH2:11][CH:12]=[CH2:13])[N:3]=1.C(Cl)Cl.[C:20](Cl)(Cl)=[O:21].[OH-].[Na+]>C1(C)C=CC=CC=1.CO>[NH2:9][C:6]1[N:7]2[O:8][C:20](=[O:21])[N:1]=[C:2]2[N:3]=[C:4]([N:10]([CH2:14][CH:15]=[CH2:16])[CH2:11][CH:12]=[CH2:13])[N:5]=1
Reactant: O=C(Cl)Cl
Reactant: C=CCN(CC=C)c1nc(N)[n+]([O-])c(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C=CCN(CC=C)c1nc(N)n2oc(=O)nc2n1
Temperature: 0 °C

Procedure:
75 g. of 2,4-diamino-6-diallylamino-s-triazine-3-oxide are suspended in 800 ml. of methylene chloride and cooled while stirring to 0° C. At this temperature there are then simultaneously added dropwise within 45 minutes 180 ml. of 20% phosgene in toluene and sufficient 10% sodium hydroxide to hold the pH at 7-7.5. The mixture is subsequently stirred for a further 1 hour. Methylene chloride and methanol are then added in order to dissolve the precipitated product. The two phases are separated and the aqueous phase is extracted twice with methylene chloride. The combined organic extracts are dried over magnesium sulfate and evaporated under reduced pressure, there being obtained 7-amino-5-diallylamino-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-2-one, having a melting point of 211°-213° C.
Reaction SMILES: [Cl-].[NH4+].[Cl:3][C:4]1[CH:5]=[C:6]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([N:31]4[CH2:36][CH2:35][CH:34]([N:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[CH2:33][CH2:32]4)=[C:25]([N+:28]([O-])=O)[CH:26]=3)[N:21]=[CH:20][C:19]=2[C:42]#[N:43])[CH:7]=[CH:8][C:9]=1[S:10][C:11]1[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=1.C(=O)(O)[O-].[Na+]>[Fe].O>[NH2:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[N:31]1[CH2:32][CH2:33][CH:34]([N:37]3[CH2:38][CH2:39][CH2:40][CH2:41]3)[CH2:35][CH2:36]1)[N:21]=[CH:20][C:19]([C:42]#[N:43])=[C:18]2[NH:17][C:6]1[CH:7]=[CH:8][C:9]([S:10][C:11]2[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=2)=[C:4]([Cl:3])[CH:5]=1
Reactant: Cn1ccnc1Sc1ccc(Nc2c(C#N)cnc3cc(N4CCC(N5CCCC5)CC4)c([N+](=O)[O-])cc23)cc1Cl
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Product: Cn1ccnc1Sc1ccc(Nc2c(C#N)cnc3cc(N4CCC(N5CCCC5)CC4)c(N)cc23)cc1Cl
Yield: 100.3 %

Procedure:
To a refluxing mixture of 0.5 g (8.95 mmol) of iron powder, 0.7 g (13.1 mmol) of ammonium chloride and 14 mL of water is added 1.26 g (2.14 mmol) of 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-6-nitro-7-(4-pyrrolidin-1-ylpiperidin-1-yl)quinoline-3-carbonitrile in portions so as to maintain gentle reflux. The resulting mixture is heated under reflux for 45 minutes. The mixture is filtered hot through a pad of Celite, washed with ethanol, and the filtrate is evaporated to dryness to yield a residue. A saturated solution of sodium bicarbonate is added to the residue, and the mixture is stirred. The solid is collected by filtration, washed with water and dried to yield 1.2 g of 6-amino-4-[3-chloro-4-(1-methyl-1H-imidazole-2-ylsulfanyl)phenylamino]-7-(4-pyrrolidin-1-yl-piperidin-1-yl)quinoline-3-carbonitrile as a yellow solid, mp 265-267° C.
Reaction SMILES: Br[C:2]1[C:15]2[CH2:14][CH2:13][N:12]3[C:8](=[N:9][C:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:11]3)[CH:7]([O:22][CH:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl-].[Li+].[CH2:32]=[CH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:29][N:26]1[CH2:27][CH2:28][CH:23]([O:22][CH:7]2[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH2:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:15]=3[CH2:14][CH2:13][N:12]3[C:8]2=[N:9][C:10]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:11]3)[CH2:24][CH2:25]1
Reactant: C=Cc1ccccc1
Reactant: CN1CCC(OC2c3cccc(Br)c3CCn3cc(-c4ccccc4)nc32)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CN1CCC(OC2c3cccc(CCc4ccccc4)c3CCn3cc(-c4ccccc4)nc32)CC1
Temperature: 95 °C
Reaction time: 20 h

Procedure:
To a solution of 8-bromo-4-(1-methyl-piperidin-4-yloxy)-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 231) (276 mg, 0, 61 mmole) in anhydrous dimethylformamide (5 mL) in a screw-capped vial are added n-tetrabutylammonium bromide (196 mg, 0, 61 mmole), lithium chloride (26 mg, 0, 61 mmole), palladium(II) acetate (27 mg, 0, 12 mmole), styrene (174 μL, 1, 5 mmole) and potassium carbonate (420 mg, 3, 0 mmoles). The vial is evacuated and filled with argon. The reaction mixture is stirred at 95° C. for 20 hours. Water and diethyl ether are added to the reaction mixture. The organic phase is washed with water, dried over magnesium sulphate, filtered and concentrated under reduced pressure. To the residue are added methanol (10 mL), 10% Pd/C (150 mg) and ammonium formate (3 g). After reflux for 1.5 hours the mixture is filtered on a celite pad, concentrated under reduced pressure, diluted with ethyl acetate, washed with water, dried over magnesium sulphate and the solvent was removed under reduced pressure. The residue is purified by preparative HPLC-MS (Waters AutoPurification HPLC/MS System, Sunfire Prep C18 5 μm OBD 30×150 mm column, eluents: water/0.1% formic acid (A) and acetonitrile/0.1% formic acid (B), focus gradient from 23% (B) to 33% (B) in 10 minutes) to afford 4-(1-methyl-piperidin-4-yloxy)-8-phenethyl-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene melting at 67° C.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O.CCCCCC>C(Cl)(Cl)Cl>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][Cl:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(SCc2ccccc2)c1
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: ClCc1cccc(SCc2ccccc2)c1
Yield: 51 %

Procedure:
One hundred milligrams of the alcohol obtained above was dissolved in 10 ml of chloroform, and 0.3 ml of thionyl chloride was added. The mixture was reacted at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 20 ml of water and 20 ml of ethyl ether. The ether layer was separated, and the solvent was evaporated. The residue was purified by medium-pressure liquid chromatography column: Lobar column, size A, Lichroprep Si 60F (a product of E. Merck Co.); eluting solvent: hexane] to give 55 mg (yield 51%) of 3-benzylthiobenzyl chloride as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][C:13]=3[N+:23]([O-:25])=[O:24])[C:9](=[O:26])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.S(=O)(=O)(O)O.Cl.[Cl:35][CH2:36]CCl>[Cl-].[Zn+2].[Cl-].O>[Cl:35][CH2:36][C:8]1[C:9](=[O:26])[N:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][C:13]=2[N+:23]([O-:25])=[O:24])[O:11][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCCl
Reactant: CCOC(=O)c1ccc(-n2oc(-c3ccccc3)cc2=O)c([N+](=O)[O-])c1
Agent: C=O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)c1ccc(-n2oc(-c3ccccc3)c(CCl)c2=O)c([N+](=O)[O-])c1
Reaction time: 1.5 h
Yield: 88 %

Procedure:
After mixing 270 g (0.762) of 5-phenyl-(4-ethoxycarbonyl-2-nitrophenyl)-4-isoxazolin-3-one prepared in the above step, 800 ml of 1,2-dichloroethane, 125 g of zinc chloride, 103 g of paraformaldehyde, and 20 ml of sulfuric acid, the reaction was performed for 1.5 hours in a steam bath while blowing hydrogen chloride gas in the reaction system. During the reaction, crystals deposited. After cooling, water was added to the reaction mixture and crystals formed were recovered by filtration, washed with water, and dried to provide 270 g of the desired product with a yield of 88%. The melting point thereof was 190° C. to 191° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@@H:8]1[CH2:12][CH2:11][C@@H:10]([C:13](=O)[NH2:14])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[C:1]([O:5][C:6](=[O:16])[NH:7][C@@H:8]1[CH2:12][CH2:11][C@@H:10]([C:13]#[N:14])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C(N)=O)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C#N)C1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In a round-bottomed flask, ((1R,3R)-3-carbamoyl-cyclopentyl)-carbamic acid tert-butyl ester (96 mg, 0.42 mmol) was suspended in THF (2.5 ml). The reaction mixture was cooled to 0° C. and triethylamine (0.28 ml, 2.01 mmol) followed by trifluoroacetic anhydride (0.095 ml, 0.67 mmol) were added. The homogeneous reaction mixture was stirred at 0° C. for 1.5 h then quenched with water and extracted with dichloromethane (2×). The combined organic layers were dried over sodium sulfate, filtered and concentrated to afford ((1R,3R)-3-cyanocyclopentyl)-carbamic acid tert-butyl ester as an off-white waxy solid which contained some triethylamine trifluoroacetate as a major impurity. This material was used without further purification.
Reaction SMILES: [C:1]1([C:7]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26]([OH:28])=O)=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][S:30]([NH2:33])(=[O:32])=[O:31]>>[C:1]1([C:7]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26]([NH:33][S:30]([CH3:29])(=[O:32])=[O:31])=[O:28])=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)C=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1
Product: CS(=O)(=O)NC(=O)C=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1

Procedure:
Prepared by coupling 2e and methylsulfonamide in accordance with Procedure 1, Method A described hereinabove. Yield (68%); 1H NMR (CDCl3) δ 7.66 (d, J=15.7 Hz, 1H), 7.18 (m, 10H), 6.95 (d, J=8.1 Hz, 2H), 6.84 (d, J=7.3 Hz, 1H), 6.28 (d, J=15.7 Hz, 1H), 3.36 (s, 3H), 2.82 (t, J=7.0 Hz, 2H), 2.41 (t, J=7.0 Hz, 2H), 2.19 (m, 2H); ESI m/z: 442 (M−H−, 100%).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:19])=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(O)(C(F)(F)F)=O>[Cl:19][C:13]1[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[CH:10][CH:11]=2)[N:16]=[CH:15][CH:14]=1
Reactant: Clc1ccnc2cc(OCc3ccccc3)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc2c(Cl)ccnc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
A solution of 7-benzyloxy-4-chloroquinoline (17 g, 56 mmol), (Konishi et al. WO 96/11187), in TFA (170 ml) was heated at reflux for 2 hours. The solvent was removed under vacuum and the residue was triturated with ether, filtered and washed with ether. The solid was suspended in an aqueous solution of sodium hydrogen carbonate (5.5 g, 65 mmol in 200 ml of water) and stirred at ambient temperature for 30 minutes. The solid was collected by filtration, washed with water and dried overnight under vacuum and over phosphorus pentoxide to give 4-chloro-7-hydroxyquinoline (9.85 g, 98%).
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)(=O)C.[OH-].[Na+]>C(O)C>[NH2:4][C:5]1[CH:6]=[C:7]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(-c2ccc(NC(C)=O)cc2-c2ccc(OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2ccc(N)cc2-c2ccc(OC)cc2)cc1

Procedure:
A solution of 10.0 g. of 4'-acetamido-4,4"-dimethoxy-1,1':2',1"-terphenyl in 250 ml. of 2B ethanol and 30 ml. of 5N sodium hydroxide was allowed to reflux overnight. Another 30 ml. of 5N sodium hydroxide were added and the reaction was allowed to reflux an additional 24 hours. The solution was then treated with 23 ml. of hydrochloric acid and evaporated in vacuo. The residue was taken up in 500 ml. of diethyl ether and 500 ml. of ethyl acetate. The organic solution was washed with water until neutral, dried over sodium sulfate, filtered, and evaporated in vacuo. The residue was crystallized from diethyl ether to provide 6.42 g. of the desired amino intermediate, m.p. about 115°-117° C.