Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[B-](F)(F)F.[CH2:6]([N+:13]1[CH:14]([C:21]([O:23][CH3:24])=[O:22])[CH2:15][CH2:16][C:17]=1OCC)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CCN(CC)CC.[CH3:32][N+:33]([O-:35])=[O:34]>C(Cl)Cl>[CH3:24][O:23][C:21]([CH:14]1[CH2:15][CH2:16][C:17](=[CH:32][N+:33]([O-:35])=[O:34])[N:13]1[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:22]
Reactant: CCOC1=[N+](Cc2ccccc2)C(C(=O)OC)CC1
Reactant: C[N+](=O)[O-]
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CCC(=C[N+](=O)[O-])N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.5 %

Procedure:
To the mixture obtained in Example 1C (0.2 mol) in 130 mL CH2Cl2 at ambient temperature was added Et3N (33.5 mL, 0.24 mol) followed by CH3NO2 (13 mL, 0.24 mol). The mixture stirred at ambient temperature for 8 h then was diluted with CH2Cl2, the layers were separated and the organic layer was washed with 20 mL 5% H2SO4 and 20 mL brine. The organic layer was dried over anhydrous Na2SO4, concentrated and purified via column chromatography (SiO2, 50% hexanes-EtOAc) to give 10.2 g of the title compound (36.9 mmol). MS (DCl/NH3) m/z 277 (M+H)+.
Reaction SMILES: [I-].[C-:2]1([CH2:7][N+](C)(C)C)[CH:6]=[CH:5][CH:4]=[CH:3]1.[CH-:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1.[Fe+2:17].[C-:18]#[N:19].[K+]>O>[C-:2]1([CH2:7][C:18]#[N:19])[CH:3]=[CH:4][CH:5]=[CH:6]1.[CH-:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1.[Fe+2:17]
Reactant: [C-]#N
Reactant: C[N+](C)(C)C[c-]1cccc1
Agent: [Fe+2]
Agent: [I-]
Agent: [K+]
Solvent: O
Product: N#CC[c-]1cccc1
Temperature: 25 °C

Procedure:
8.00 g (20.8 mmol) of ferrocenylmethyltrimethylammonium iodide (Strem) and 8 g of KCN (123 mmol) are dissolved in 80 ml of water. The mixture is placed in a round-bottomed flask surmounted by a reflux condenser. The mixture is heated at reflux for 2 hours and is then allowed to cool to room temperature. The product is extracted with 3 times 40 ml of ethyl ether. The organic phase is washed first with 2 times 30 ml of water and then dried over magnesium sulfate. After filtration and evaporation, 4.1 g of ferrocenylacetonitrile are collected.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[F:22][C:23]1[CH:24]=[CH:25][C:26]([O:32][CH3:33])=[C:27](B(O)O)[CH:28]=1.C([O-])(O)=O.[Na+].CCO>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.O>[F:22][C:23]1[CH:28]=[CH:27][C:26]([O:32][CH3:33])=[C:25]([C:2]2[S:6][C:5]([S:7]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[NH:21][N:20]=[N:19][N:18]=4)[CH:12]=3)(=[O:9])=[O:8])=[CH:4][CH:3]=2)[CH:24]=1
Reactant: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)s1
Reactant: COc1ccc(F)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(F)cc1-c1ccc(S(=O)(=O)Nc2cccc(-c3nnn[nH]3)c2)s1
Temperature: 80 °C
Yield: 19 %

Procedure:
A mixture of 5-bromo-N-[3-(1H-tetrazol-5-yl)phenyl]thiophene-2-sulfonamide (Intermediate 17) (19 mg, 0.05 mmol), 5-fluoro-2-methoxyphenylboronic acid (10 mg, 0.06 mmol), Pd(PPh3)4 (3 mg, 0.0025 mmol), NaHCO3 (13 mg, 0.15 mmol), EtOH (750 μL) and water (250 μL) was heated in a sealed tube at 80° C. over night. The mixture was concentrated and purified by preparative HPLC (ACE C8 5 μm, 0.1% TFA in water/CH3CN) giving 4.1 mg (19%) of the title compound. MS (ESI+) calcd for C18H14FN5O3S2 431.052209, found 431.051439.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][CH:7]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19]N(CC)CC)=[CH:13][CH:12]=1)[CH2:8][CH2:9][CH3:10])=[O:5])#[N:2].NC(C1C=CC(OCC[O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][N:43]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=CC=1)CCC>>[C:1]([CH2:3][C:4]([NH:6][CH:7]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][N:43]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C:44]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:45])=[CH:15][CH:16]=1)[CH2:8][CH2:9][CH3:10])=[O:5])#[N:2]
Reactant: CCCC(NC(=O)CC#N)c1ccc(OCCN(CC)CC)cc1
Reactant: CCCC(N)c1ccc(OCCOCCOCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Product: CCCC(NC(=O)CC#N)c1ccc(OCCOCCOCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared by using a similar procedure as described for the preparation of 29 except that (2-(2-(2-(4-(1-aminobutyl)phenoxy)ethoxy)ethoxy)ethyl)imidodicarbonic acid, 1,3-bis-tert-butyl ester (45) was used instead of 1-(4-(2-(diethylamino)ethoxy)phenyl)butan-1-amine (25). This produced the crude product which was purified by flash silica gel column chromatography, eluting with 3:2 hexanes/ethyl acetate, to give 46 (95 mg, 84%) as a clear oil: MS (ES+) m/z 564.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10](O)=[O:11])=[CH:8][N:7]=[C:6]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:5]=12)[CH3:2].S(Cl)([Cl:20])=O>>[CH2:1]([O:3][C:4]1[C:9]([C:10]([Cl:20])=[O:11])=[CH:8][N:7]=[C:6]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:5]=12)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOc1c(C(=O)O)cnc2c1cnn2CC
Product: CCOc1c(C(=O)Cl)cnc2c1cnn2CC

Procedure:
117.5 g. of 4-ethoxy-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (0.5 mol.) are slowly added with stirring to 300 ml. of thionyl chloride. The mixture is refluxed for 4 hours, excess thionyl chloride is removed in vacuo and the residue dissolved in 500 ml. anhydrous diethylether. The undissolved material is filtered off and the filtrate intensively cooled. The acid chloride precipitates; it is filtered under suction and washed well with cold water. Yield 105 g. (80%), m.p. 72°-73°.
Reaction SMILES: CC([N:5]([C@H:9]1[CH2:14][CH2:13][C@@H:12]([C:15]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([F:28])([F:27])[F:26])=[O:16])[CH2:11][CH2:10]1)C(=O)[O-])(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:5][C@@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([F:26])([F:27])[F:28])=[O:16])[CH2:13][CH2:14]1
Reactant: CC(C)(C)N(C(=O)[O-])[C@H]1CC[C@@H](C(=O)NCc2ccccc2C(F)(F)F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CC[C@@H](C(=O)NCc2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
A 500 mL round bottom flask equipped with a magnetic stir bar was charged with 1,1-dimethylethyl{cis-4-[({[2-(trifluoromethyl)phenyl]methyl}amino)carbonyl]cyclohexyl}carbamate (24.88 g, 62.1 mmol) and dichloromethane (100 mL). Trifluoroacetic acid (100 mL) was added slowly, and the reaction mixture was stirred at room temperature for 1 h. The volatile components were removed by rotary evaporation, and the crude oil was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution (3×200 mL). The organic phase was dried over Na2SO4, filtered and concentrated to give 18.3 g of the title compound (98%) as an off-white solid. MS (ES) m/e 301 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][CH:16]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:15][CH2:14]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.O.[OH-].[Na+]>ClCCl>[CH2:12]1[C:11]2([CH2:14][CH2:15][CH:16]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:17][CH2:18]2)[CH2:10][CH2:9][NH:8][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3ccc(Cl)c(Cl)c3)CC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(NC2CCC3(CCNCC3)CC2)cc1Cl
Temperature: 25 °C
Yield: 83.9 %

Procedure:
To an ice-cooled solution of 9-(3,4-dichloro-phenylamino)-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (258 mg, 0.624 mmol) in dichloromethane (10 mL) a solution of trifluoroacetic acid (4 mL) in dichloromethane (5 mL) was added. The mixture was stirred a room temperature over night. Water was added followed by sodium hydroxide 3 M to pH 9-10. The aqueous layer was extracted with dichloromethane (4×40 mL). The combined organic layers were washed with brine, dried with sodium sulphate and evaporated to give (3-aza-spiro[5.5]undec-9-yl)-(3,4-dichloro-phenyl)-amine (164 mg 84%) as a brownish solid. Mp. 128-132° C.
Reaction SMILES: Br[CH:2]=[C:3]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.[CH3:32][N:33]1[CH2:46][CH2:45][C:36]2[NH:37][C:38]3[CH:39]=[CH:40][C:41]([CH3:44])=[CH:42][C:43]=3[C:35]=2[CH2:34]1>CN(C=O)C.[Cu]I>[CH3:32][N:33]1[CH2:46][CH2:45][C:36]2[N:37](/[CH:2]=[C:3](\[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)/[C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[C:38]3[CH:39]=[CH:40][C:41]([CH3:44])=[CH:42][C:43]=3[C:35]=2[CH2:34]1
Reactant: BrC=C(c1ccccc1)c1ccncc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2/C=C(\c2ccccc2)c2ccncc2)CCN(C)C1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
4-(2-Bromo-1-phenylvinyl)pyridine (310 mg, 1.1 mmol) was dissolved in DMF (5 mL) and potassium phosphate (424 mg, 2 mmol) was added followed by copper (I) iodide (19 mg, 0.1 mmol) and L-proline (23 mg, 0.2 mmol). 2,3,4,5-Tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (200 mg, 1 mmol) was added and the mixture purged with nitrogen for 2 min. The reaction mixture was stirred at 85° C. overnight. Water was added and the solid mass was filtered under vacuum. The crude product was purified on silica gel (100-200 mesh) using 0-10% MeOH:DCM as eluent. The compound was further purified through reverse phase HPLC. Yield: 15 mg. 1H NMR (CDCl3, free base) δ (ppm): 8.60 (d, 2H), 7.30-7.15 (m, 7H), 7.0 (m, 3H), 6.90 (d, 1H), 3.70 (s, 2H), 2.70 (m, 2H), 2.50 (s, 3H), 2.42 (s, 3H), 2.36 (m, 2H).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:11]([Si:13]([CH3:16])([CH3:15])[CH3:14])#[CH:12].C(N(C(C)C)CC)(C)C>CN(C=O)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.[Cu]I>[CH3:14][Si:13]([C:11]#[C:12][C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)([CH3:16])[CH3:15]
Reactant: C#C[Si](C)(C)C
Reactant: Brc1cnc2cccnn12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)C#Cc1cnc2cccnn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
A mixture of 3-bromoimidazo[1,2-b]pyridazine (36.78 g, 0.186 mol; prepared according to Stanovnik, B. et al. Synthesis (1981), 12, 987-989), ethynyltrimethylsilane (21.89 g, 0.223 mol), Pd(PPh3)4 (10.73 g, 9.29 mmol), CuI (5.30 g, 0.028 mol), and diisopropylethylamine (32.4 mL, 0.279 mol) in 150 mL of DMF was stirred at ambient temperature, under an atmosphere of N2, for 1 h. The reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (eluted with 0-5% MeOH/DCM) to provide 28.46 g of product.
Reaction SMILES: [N+:1]([CH:4]=[C:5]1[NH:10][CH2:9][CH2:8][CH2:7][NH:6]1)([O-:3])=[O:2].[CH2:11](N)[CH2:12][CH2:13]N.C(Br)C=C>>[N+:1]([CH:4]=[C:5]1[NH:10][CH2:9][CH2:8][CH2:7][N:6]1[CH2:13][CH:12]=[CH2:11])([O-:3])=[O:2]
Reactant: O=[N+]([O-])C=C1NCCCN1
Reactant: NCCCN
Solvent: C=CCBr
Product: C=CCN1CCCNC1=C[N+](=O)[O-]

Procedure:
Method B, reacting hexahydro-2-(nitromethylene)pyrimidine (HNMP), prepared by Method A by reaction of NKDM with 1,3-propanediamine, with allyl bromide. Melting point: 125°-126°C.
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]=1[OH:17])([CH3:6])([CH3:5])[CH3:4].Cl[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.Cl>CS(C)=O>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([C:11]2[CH:12]=[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[C:8]([OH:17])=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=2)=[CH:20][CH:21]=1)([O-:27])=[O:26]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(-c2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Temperature: 90 °C
Reaction time: 17 h
Yield: 68.1 %

Procedure:
A mixture of 12.0 g (300 mmol) of powdered sodium hydroxide, 24.7 g (120 mmol) of 2,6-di-tert-butylphenol, 15.7 g (100 mmol) of 1-chloro-4-nitrobenzene, and 120 mL of DMSO was stirred for 17 hours at 90° C. and poured into one liter of 1N HCl. The resulting aqueous mixture was extracted with three 250 mL portions of diethyl ether. Combination, drying (MgSO4), and concentration of the organic layers afforded a residue which was purified by two recrystallizations from ethanol-dichloromethane to give 22.3 g (68% yield) of 4-(4'-nitrophenyl)-2,6-di-tert-butylphenol which an also be named 3,5-bis-(1,1-dimethylethyl)-4'-nitro-(1,1'-biphenyl)-4-ol.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:18][C:19]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:20]=1[NH2:21]>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:21][C:20]1[C:22]([CH3:26])=[CH:23][CH:24]=[CH:25][C:19]=1[CH3:18])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(C)cccc2c1Cl
Reactant: Cc1cccc(C)c1N
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(C)cccc2c1Nc1c(C)cccc1C

Procedure:
3-Butyryl-4-chloro-8-methylquinoline (2.48 g, 10 mmol) and 2,6-dimethylaniline (1.85 ml, 15 mmol) in dioxan (10 ml) were heated at reflux for 30 minutes, then the solvent evaporated and the product converted to free base. Recrystallisation from aqueous ethanol gave 3-butyryl-4-(2,6-dimethylphenylamino)-8-methylquinoline, m.p. 100°-101°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]([CH2:19][CH3:20])[C:10](=[O:21])[C:9]=2[NH:22]C(=O)OCC)[CH:5]=[CH:6][CH:7]=1>C(O)C.O>[NH2:22][C:9]1[C:10](=[O:21])[N:11]([CH2:19][CH3:20])[C:12]2[C:17]([C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=2
Reactant: CCOC(=O)Nc1c(-c2cccc(Cl)c2)c2ccc(C)nc2n(CC)c1=O
Solvent: CCO
Solvent: O
Product: CCn1c(=O)c(N)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Temperature: 100 °C

Procedure:
A 720 mg portion of ethyl N-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]carbamate was stirred in 40 ml of an ethanol-3M sodium hydroxide aqueous solution (1:1) under heating at an oil bath temperature of 100° C. for 4 hours. After cooling to room temperature, the reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was washed with saturated brine and the solvent was evaporated. The resulting residue was purified by a silica gel column chromatography (toluene-ethyl acetate) and then recrystallized from diisopropyl ether-ethyl acetate to obtain 298 mg of 3-amino-4-(3-chlorophenyl)-1-ethyl-7-methyl-1,8-naphthyridin-2(1H)-one as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[F:59][C:60]([F:81])([F:80])[C:61]1[N:66]=[CH:65][C:64]([C:67]2[C:79]3[C:78]4[C:73](=[CH:74][CH:75]=[CH:76][CH:77]=4)[NH:72][C:71]=3[CH:70]=[CH:69][CH:68]=2)=[CH:63][CH:62]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:10][C:4]1[CH:3]=[C:2]([N:72]2[C:71]3[CH:70]=[CH:69][CH:68]=[C:67]([C:64]4[CH:65]=[N:66][C:61]([C:60]([F:81])([F:59])[F:80])=[CH:62][CH:63]=4)[C:79]=3[C:78]3[C:73]2=[CH:74][CH:75]=[CH:76][CH:77]=3)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: FC(F)(F)c1ccc(-c2cccc3[nH]c4ccccc4c23)cn1
Reactant: N#Cc1ccc(Br)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: N#Cc1ccc(-n2c3ccccc3c3c(-c4ccc(C(F)(F)F)nc4)cccc32)cc1F
Temperature: 25 °C
Yield: 49.6 %

Procedure:
0.52 g of 4-bromo-2-fluorobenzonitrile, 2.14 g of caesium carbonate, 0.12 g of (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) and 39 mg of palladium acetate are successively added, under argon, to a solution of 0.54 g of 4-[6-(trifluoromethyl)pyridin-3-yl]-9H-carbazole in 50 ml of dioxane. The reaction mixture is refluxed for 6 hours, cooled to ambient temperature, filtered through celite and concentrated under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a mixture of cyclohexane and ethyl acetate (96/4 by volume) so as to give 0.37 g of 2-fluoro-4-{4-[6-(trifluoro-methyl)pyridin-3-yl]-9H-carbazol-9-yl}benzonitrile in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[N+:12]([O-])=O>CO.[Pd]>[NH2:12][C:3]1[CH:4]=[CH:5][C:6]2[NH:7][C:8](=[O:11])[O:9][C:10]=2[C:2]=1[CH3:1]
Reactant: Cc1c([N+](=O)[O-])ccc2[nH]c(=O)oc12
Agent: [Pd]
Solvent: CO
Product: Cc1c(N)ccc2[nH]c(=O)oc12
Yield: 97.8 %

Procedure:
7-Methyl-6-nitro-3H-benzoxazol-2-one (0.895 g, 4.61 mmol) was hydrogenated in Methanol (30.0 mL) over 10% Palladium on Carbon (50% Wet) (0.135 g, 0.0634 mmol) under an atmosphere of Hydrogen (30 psi) for 2 h. The mixture was filtered through Celite, washed with MeOH and conc. in vacuo to afford 6-Amino-7-methyl-3H-benzoxazol-2-one (0.74 g, 98%).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[C:24]([F:32])[CH2:25][CH:26]1SCCCS1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[B-](F)(F)F.C[O+:39](C)C.C(=O)([O-])[O-].[Ca+2].[BH4-].[Na+]>C(Cl)Cl.C(O)C.C(O)(=O)C.CC(C)=O.O>[Si:1]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[C:24]([F:32])[CH2:25][CH2:26][OH:39])([C:14]([CH3:15])([CH3:17])[CH3:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[Si](OCCCCC=C(F)CC1SCCCS1)(c1ccccc1)c1ccccc1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: CC(C)(C)[Si](OCCCCC=C(F)CCO)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 48.8 %

Procedure:
To a solution of the dithialane prepared in 2F (0.424 g, 0.86 mmoles) in dry methylene chloride (4 ml) was added at room temperature trimethyloxonium tetrafluoroborate (0.125 g, 0.86 mmoles) and the mixture was stirred for 1 hr. Then a 9:1 mixture of acetone and water (2 ml) containing calcium carbonate (0.172 g, 1.72 mmoles) was added and the mixture was stirred overnight at room temperature. The precipitate was filtered off and after dilution with saturated brine the mixture was extracted three times with ether. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford an oil. The resulting oil was dissolved in ethanol (5 ml) and sodium borohydride (19 mg, 0.50 mmoles) was added. The mixture was stirred for 30 min at 0° C. The excess of sodium borohydride was treated with acetone, the mixture was acidified with acetic acid and concentrated under reduced pressure. The residue was taken up with water and extracted three times with ether. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford an oil. Flash chromatography on silicagel and elution with a 25:75 mixture of ethyl acetate and hexane afforded the desired alcohol as an oil (0.168 g, 49%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH:15]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)[CH2:20][CH2:19]2)=[O:17])([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>CO>[F:44][C:41]1[CH:42]=[CH:43][C:38]([CH:15]([C:11]2([OH:14])[CH2:10][CH2:9][N:8]([CH3:6])[CH2:13][CH2:12]2)[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)[CH2:20][CH2:19]2)=[O:17])=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C(C(=O)N2CCN(CCCCc3cccc4ccccc34)CC2)c2ccc(F)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CN1CCC(O)(C(C(=O)N2CCN(CCCCc3cccc4ccccc34)CC2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.3 %

Procedure:
1.04 g of 1-t-Butoxycarbonyl-4-{1-(4-fluorophenyl)-2-[4-(naphthalen-1-yl-butyl)piperazin-1-yl]-2-oxoethyl}-4-hydroxypiperidine was dissolved in 10 ml of methanol, and 20 ml of 4M hydrogen chloride/1,4-dioxane solution was added, followed by stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with 1M aqueous sodium hydroxide solution and a saturated aqueous sodium solution. The organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in 9 ml of acetonitrile, and 640 μl of 37% formalin, 190 μl of acetic acid and 160 mg of sodium cyanoborohydride were added, followed by stirring at room temperature for an hour. The reaction solution was diluted with ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (Chromatorex NH, hexane:ethyl acetate=2:1) to give 0.44 g of 4-{1-(4-fluorophenyl)-2-[4-(naphthalen-1-yl-butyl)piperazin-1-yl]-2-oxoethyl}-1-methylpiperidin-4-ol as an oil.
Reaction SMILES: C(OC([O:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=O)(C)(C)C.[CH3:16][O:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22]([CH3:27])=[N:23][NH:24]2)=[CH:20][CH:19]=1.C(N(CC)CC)C>C(#N)C.CN(C1C=CN=CC=1)C>[C:12]([O:11][C:9]([O:8][N:24]1[C:25]2[C:21](=[CH:20][CH:19]=[C:18]([O:17][CH3:16])[CH:26]=2)[C:22]([CH3:27])=[N:23]1)=[O:10])([CH3:13])([CH3:14])[CH3:15]
Reactant: COc1ccc2c(C)n[nH]c2c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc2c(C)nn(OC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Di-tert-butyl-dicarbonate in acetonitrile was mixed at 0° C. with 6-methoxy-3-methyl-1H-indazole (prepared following the procedure described by F. Dennler, Tetrahedron, 22, 1966, 3131-3139) (26.27 g, 0.162 mol), acetonitrile (200 ml), triethylamine (25 ml, 0.178 mol), DMAP (3.96 g, 0.0324 mol). The mixture was stirred at room temperature overnight. Acetonitrile was concentrated under vacuum. The mixture was extracted with ethylacetate and acidified at pH=2 with a solution of concentrated HCl, dried over Na2SO4, filtered and put in diisopropylether. 23.9 g of the expected product were obtained (as solid, 59%).