Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=O)[NH:14][N:15]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:18]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=[S:18])[NH:14][N:15]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cc1c(Cl)cc(-c2ccc(=O)[nH]n2)cc1Cl
Solvent: c1ccncc1
Product: Cc1c(Cl)cc(-c2ccc(=S)[nH]n2)cc1Cl
Temperature: 25 °C
Yield: 55.9 %

Procedure:
12.75 g of 6-(3,5-dichloro-4-methylphenyl)-3-pyridazone and 22 g of phosphorus pentasulphide in 80 ml of pyridine were heated under reflux on an oil bath for 7 hours. The reaction mixture was then cooled to room temperature and its volume was reduced by one-half by distilling off the pyridine under reduced pressure. 300 ml of ethyl acetate were added to the residue and the mixture was poured into ice-water. After stirring the mixture for a short time, the resulting yellow solid was collected by filtration, washed with water and dried to give 7.5 g (56%) of the desired compound. After recrystallizing the compound from a 10:1 by volume mixture of ethanol and dioxan, the compound melted at 255°-258° C.
Reaction SMILES: [Li]CCCC.CCCCCC.[CH3:12][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.Cl[Si](CC)(CC)CC.[Cl:26][C:27]1[N:36]=[C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:44]([C:46]3[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=3)=[O:45])[CH:33]=2)[N:28]=1>C1COCC1.CCOC(C)=O.O>[Cl:26][C:27]1[N:36]=[C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:44]([C:46]3[CH:47]=[CH:48][C:49]([F:52])=[CH:50][CH:51]=3)([C:17]3[N:13]([CH3:12])[CH:14]=[N:15][CH:16]=3)[OH:45])[CH:33]=2)[N:28]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc2nc(Cl)nc(-c3cccc(Cl)c3)c2c1
Reactant: Cn1ccnc1
Agent: CC[Si](Cl)(CC)CC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1cncc1C(O)(c1ccc(F)cc1)c1ccc2nc(Cl)nc(-c3cccc(Cl)c3)c2c1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 0.8 %

Procedure:
BuLi 1.6M in hexane (46.5 ml, 0.0744 mol) was added dropwise at −70° C. to a mixture of 1-methyl-1H-imidazole (0.0744 mol) in THF (70 ml) under N2 flow. Chlorotriethyl-silane (0.0765 mol) was added dropwise at −70° C. The mixture was stirred at −70° C. for 15 minutes. BuLi 1.6M in hexane (41 ml, 0.0659 mol) was added dropwise at −70° C. The mixture was stirred at −70° C. for 15 minutes. A solution of intermediate 6 (0.0425 mol) in THF (150 ml) was added dropwise at −70° C. The mixture was stirred at −70° C. for 1 hour and poured out into water. EtOAc was added. The mixture was extracted with EtOAc. The organic layer was washed twice with water, separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (15-35 μm) (eluent: DCM/MeOH/NH4OH 97/3/0.5). The pure fractions were collected and the solvent was evaporated. Part (0.5 g) of the residue (14.6 g, 72%) was crystallized from 2-propanone/CH3CN. The precipitate was filtered off and dried under a vacuo, yielding 0.17 g of 2-chloro-4-(3-chlorophenyl)-α-(4-fluorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinazolinemethanol (intermediate 7), mp. 212° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:16]3[CH:12]([CH2:13][N:14](C(OC=C)=O)[CH2:15]3)[C:11](=[O:22])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[ClH:30]>O1CCOCC1>[ClH:30].[F:29][C:25]1[CH:24]=[C:23]([C:8]2([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH:16]3[CH:12]([CH2:13][NH:14][CH2:15]3)[C:11](=[O:22])[CH2:10][CH2:9]2)[CH:28]=[CH:27][CH:26]=1
Reactant: C=COC(=O)N1CC2C(=O)CCC(c3cccc(F)c3)(c3cccc(F)c3)C2C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1CCC(c2cccc(F)c2)(c2cccc(F)c2)C2CNCC12
Temperature: 60 °C
Reaction time: 16 h

Procedure:
(3aRS,7aRS)-7,7-bis-(3-fluorophenyl)-2-vinyloxycarbonyl-4-perhydroisoindolone (64.5 g) is treated with a 6N solution (330 cc) of hydrochloric acid in dioxane for 30 minutes at 25° C. The solution is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is taken up in ethanol (500 cc). The solution is heated at 60° C. for 6 hours and stirred for 16 hours at 25° C. and then concentrated to half its volume under reduced pressure (2.7 kPa) and the crystals formed are drained and washed with isopropyl ether and then dried. 7,7-Bis(3-Fluorophenyl)-4-perhydroisoindolone hydrochloride (48.7 g) is obtained. m.p.=264° C.
Reaction SMILES: [C:1]([C:5]1[C:10]([OH:11])=[C:9]([CH3:12])[C:8]([CH3:13])=[C:7]([CH2:14]N(C)C)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[P:18]([O-:57])([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].[NH2-].[Li+].CNC>CN(C)C=O.C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.C(O)(=O)C.C1C=CC=CC=1>[C:1]([C:5]1[C:10]([OH:11])=[C:9]([CH3:12])[C:8]([CH3:13])=[C:7]([CH:6]=1)[CH2:14][P:18](=[O:57])([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCCCCCOP([O-])OCCCCCCCCCCCCCCCCCC
Reactant: Cc1c(CN(C)C)cc(C(C)(C)C)c(O)c1C
Agent: CNC
Agent: [Li+]
Agent: [NH2-]
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOP(=O)(Cc1cc(C(C)(C)C)c(O)c(C)c1C)OCCCCCCCCCCCCCCCCCC

Procedure:
To 37.6 grams of the compound of Example 1 and 94 grams of di-n-octadecyl phosphite dissolved in 100 ml of dry N,N-dimethylformamide at 55° to 60° was added 2.16 grams of lithium amide and the reaction temperature raised to 106° and kept at 105° to 107° for 11/4 hours, the evolved dimethylamine being swept out of the reaction mixture by a stream of nitrogen. The reaction mixture was dissolved in about one liter of a solvent mixture of toluene, chloroform and benzene containing 6 grams of acetic acid, filtered free of some insoluble by-product. The clear filtrate was washed successively with water, 6N aqueous hydrochloric acid, and water until the wash water was in the pH range of 5 to 6. The solvent solution of the product was dried over anhydrous sodium sulfate. After removing the drying agent by filtration, the clear filtrate was freed of solvent by distillation at reduced pressures yielding a solid residue which afforded the desired compound as white crystals at 91° to 93° after crystallization from isopropanol (Compound 2).
Reaction SMILES: [NH2:1][CH2:2][O:3][C:4]1[N:9]=[CH:8][CH:7]=[CH:6][N:5]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl[CH2:19][CH2:20][O:21][CH2:22][CH2:23]Cl>COCCOCCOC>[N:1]1([CH2:2][O:3][C:4]2[N:9]=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: ClCCOCCCl
Reactant: NCOc1ncccn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: COCCOCCOC
Product: c1cnc(OCN2CCOCC2)nc1
Temperature: 110 °C
Yield: 27.3 %

Procedure:
The aminomethyl-pyrimidinyl ether (1.88 g, 4.94 mmol) was suspended in 14.0 mL anhydrous 2-methoxyethyl ether. Potassium carbonate was added (0.81 g, 5.85 mmol), then a catalytic amount of sodium iodide and finally 2-chloroethyl ether (0.58 g, 4.95 mmol). The reaction was heated in a 110° C. bath for 12 h under an inert atmosphere, then allowed to cool. The reaction was then partitioned between water and dichloromethane, the pH adjusted to ˜7 with ammonium chloride aqueous solution. The organics were dried with MgSO4, filtered and concentrated in vacuo. The residue (containing some 2-methoxyethyl ether) was purified by column chromatography on silica gel using 0-10% MeOH in dichloromethane eluent mixtures to provide 610 mg of desired morpholinylmethyl-pyrimidinyl ether (main fraction, 1.35 mmol, 27%) as a brown foam. Also isolated was lower Rf material, which was the de-BOC product (˜150 mg).
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:13][C:14]1[C:22]([F:23])=[C:21]([F:24])[CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17].S(=O)(=O)(O)O>C(Cl)(Cl)(Cl)Cl.C(O)C.C1(C)C=CC=CC=1>[F:13][C:14]1[C:22]([F:23])=[C:21]([F:24])[CH:20]=[CH:19][C:15]=1[C:16]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[O:17]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(Cl)c1ccc(F)c(F)c1F
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1ccc(F)c(F)c1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3.6 g (0.148 mol) of magnesium filings are introduced into 8.1 ml of ethanol, the reaction is started up using a few drops of carbon tetrachloride, and a solution of 21.8 g (0.136 mol) of diethyl malonate in 15 ml of ethanol and 58 ml of toluene is subsequently added dropwise in such a manner that the internal temperature is between 50 and 60° C. Stirring is subsequently continued for one hour at 60° C. A solution of 27.6 g (0.15 mol) of 2,3,4-trifluorobenzoyl chloride in 15.4 ml of toluene is added dropwise at -10° to -5° C., and stirring is continued for one hour at 0° C. and subsequently overnight, allowing the mixture to come to room temperature. The batch is poured into 60 ml of ice-water, treated with 9.7 ml of concentrated sulphuric acid and extracted using toluene. The toluene phase is washed with saturated sodium chloride solution and the solvent is removed in vacuo.
Reaction SMILES: [CH:1]1([CH:4]([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)O)[CH2:3][CH2:2]1.[ClH:13]>C(O)(=O)C>[Cl:13][CH2:3][CH2:2][CH:1]=[CH:4][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1
Reactant: Cl
Reactant: OC(c1ccc(F)cc1)C1CC1
Solvent: CC(=O)O
Product: Fc1ccc(C=CCCCl)cc1

Procedure:
Reduction of cyclopropyl 4-fluorophenyl ketone by reaction with sodium borohydride gave cyclopropyl-4-fluorophenylcarbinol. Reaction of the cyclopropyl carbinol with hydrogen chloride in acetic acid effected opening of the cyclopropyl ring, chlorination and dehydration to afford 1-chloro-4-(4-fluorophenyl)-3-butene. The chlorobutene was reacted with dimethylamine in ethanol at 100° C. for forty-eight hours to provide N,N-dimethyl-4-(4-fluorophenyl)-3-butenylamine. A solution of 54.4 g. of the butenylamine in 343 ml. of ethanol containing 2.5 g. of Raney Nickel was hydrogenated to provide 47.71 g. of N,N-dimethyl-4-(4-fluorophenyl)butylamine. B.P. 115°-118° C. at 12 torr.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]3[CH2:23][CH:22]([CH2:24][NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:21][C:20]3=[O:32])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH2:33].[OH-].[Li+]>O.C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([S:15]([NH:18][CH:19]([CH2:23][CH:22]([OH:33])[CH2:24][NH:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:20]([OH:21])=[O:32])(=[O:16])=[O:17])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc(S(=O)(=O)NC3CC(CNc4ccccc4)OC3=O)cc2)cc1
Reactant: O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CNc3ccccc3)C(=O)O)cc2)cc1
Reaction time: 4 h

Procedure:
To a solution of 3-[(4′-Methoxy[1,1′-biphenyl]-4-yl)sulfonyl]amino-2-oxo-5-[(phenylamino)methyl]-tetrahydrofuran 19a (0.19 g, 0.42 mmol) in water (3 mL) and THF (3 mL) is added slowly lithium hydroxide monohydrate (180 mg, 4.2 mmol). The reaction mixture is stirred for 4 h, and then concentrated to dryness. The resulting mixture is diluted with water, and then the mixture is extracted twice with Et2O. The Et2O layer is discarded and the aqueous layer is neutralized carefully with 1N HCl to pH 6, then extracted three times with EtOAc. The combined EtOAc layer is washed with brine, dried over MgSO4 and concentrated to a solid which is recrystallized from EtOAc/hexane (3:7) to give the desired product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[N:5][CH:4]=1.[N+:13]([O-])([O-:15])=[O:14].[K+]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[N:5][C:4]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])[O-]
Reactant: COc1cncc2ccccc12
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COc1c([N+](=O)[O-])ncc2ccccc12
Temperature: 60 °C
Reaction time: 2 h
Yield: 34.8 %

Procedure:
To a solution of 4-methoxyisoquinoline (130 mg, 0.82 mmol) in 98% sulfuric acid (0.61 mL) was added potassium nitrate (91 mg, 0.90 mmol), and the mixture was heated to 60° C. and stirred for 2 hours. The reaction solution was cooled, and then thereto was added ice. The powders were filtered to dissolve in ethyl acetate. The solution was washed with aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate, followed by concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→2:8) to give 4-methoxy-3-nitroisoquinoline (58.3 mg, 35%) as a pale yellow powder.
Reaction SMILES: [OH:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Br:19][CH2:20][C:21](Br)=[O:22].N1C=CC=CC=1>>[CH3:7][O:6][C:4](=[O:5])[CH2:3][C@H:2]([O:1][C:21](=[O:22])[CH2:20][Br:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCC[C@@H](O)CC(=O)OC
Reactant: O=C(Br)CBr
Solvent: c1ccncc1
Product: CCCCCCCCCCC[C@H](CC(=O)OC)OC(=O)CBr
Yield: 89.8 %

Procedure:
To a rapidly-stirred slurry of 1.29 g (4.99 mmol) methyl (R)-3-hydroxytetradecanoate and 0.45 mL (5.2 mmol) bromoacetyl bromide in 25 mL hexanes at 0° C. in a flame-dried flask under N2 was added 0.42 mL (5.2 mmol)pyridine all at once. The mixture was removed from the cold bath for 30 min. The mixture was suction filtered through celite, washing with 75 mL ether. The filtrate was washed with 2×100 mL H2O and with 50 mL 10% NaHCO3. The ether was dried over MgSO4 and removed by rotary evaporation, giving 1.70 g (90%) crude (R)-3-[(bromoacetyl)oxy]tetradecanoic acid methyl ester as a yellow oil. Analytically pure samples could be prepared by subjecting the oil to radial chromatography, eluting with CH2Cl2.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C:7]([CH3:41])([CH3:40])[C:8](=[O:39])[N:9]2[CH:12]2[CH2:17][CH2:16][N:15]([C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][C@H:33]([CH3:37])[CH2:34][CH2:35][OH:36])=[CH:22][C:21]=3[F:38])=[O:19])[CH2:14][CH2:13]2)=[N:4][CH:3]=1.[Br-].[K+].Cl[O-].[Na+].Cl.Cl([O-])=[O:49].[Na+]>C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C:7]([CH3:40])([CH3:41])[C:8](=[O:39])[N:9]2[CH:12]2[CH2:13][CH2:14][N:15]([C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][C@H:33]([CH3:37])[CH2:34][C:35]([OH:49])=[O:36])=[CH:22][C:21]=3[F:38])=[O:19])[CH2:16][CH2:17]2)=[N:4][CH:3]=1
Reactant: C[C@H](CCO)Oc1ccccc1-c1ccc(C(=O)N2CCC(N3C(=O)C(C)(C)Cc4ncc(Cl)cc43)CC2)c(F)c1
Reactant: [O-][Cl+][O-]
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H](CC(=O)O)Oc1ccccc1-c1ccc(C(=O)N2CCC(N3C(=O)C(C)(C)Cc4ncc(Cl)cc43)CC2)c(F)c1
Reaction time: 1 h
Yield: 66.6 %

Procedure:
Under ice cooling, to a mixed solvent solution of 7-chloro-1-{1-[(3-fluoro-2′-{[(1R)-3-hydroxy-1-methylpropyl]oxy}biphenyl-4-yl)carbonyl]piperidin-4-yl}-3,3-dimethyl-3,4-dihydro-1,5-naphthyridin-2(1H)-one (296 mg) in ethyl acetate (6 ml) and water (2 ml) were added 2,2,6,6-tetramethyl-1-piperidyloxy radical (4.0 mg) and potassium bromide (60.7 mg). To this was added dropwise a 5% aqueous sodium hypochlorite solution (0.812 ml), followed by stirring for 1 hour. 1 N hydrochloric acid was added to adjust the pH to around 4, and then 79% sodium chlorite (73.0 mg) was added, and stirred at room temperature for 3 hours. To the reaction solution were added water, a saturated aqueous sodium sulfite solution and a 10% aqueous citric acid solution, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford (3R)-3-[(4′-{[4-(7-chloro-3,3-dimethyl-2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)piperidin-1-yl]carbonyl}-3′-fluorobiphenyl-2-yl)oxy]butanoic acid (202 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC([B-](C2C=CC(C)=CC=2)(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.C1(C)C(C)=CC=CC=1>[C:2]1([N:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccccc1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1C
Product: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Yield: 92 %

Procedure:
A 100-ml four-necked flask was equipped with a stirrer, a thermometer and a reflux condenser. 5.403 g (48 mmol) of chlorobenzene, 6.769 g (40 mmol) of diphenylamine, 4.613 g (48 mmol) of sodium-tert-butoxide, 0.002 g (0.01 mmol) of palladium (II) acetate and 5 ml of xylene were weighed in the flask, followed by stirring. Further, 0.023 g (0.04 mmol) of tri-tert-butylphosphonium tetra-para-tolylborate obtained in Example B-3 was weighed in air and added into the flask. The flask was purged with argon, followed by stirring at 100-120° C. for 10 hours. After the completion of the reaction, 45 ml of xylene and 50 ml of saturated sodium chloride solution were added, followed by separation. The organic phase was purified by column chromatography to afford 9.028 g of triphenylamine (yield: 92 mol % based on diphenylamine). The melting point was 125-126° C.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1>>[Cl:10][C:11]1[CH:16]=[C:15]([C:2]2[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C(O)c1ccc(Br)o1
Product: O=C(O)c1ccc(-c2cccc(Cl)c2)o1

Procedure:
5-Bromo-2-furoic acid (1 g, 5.8 mmol) was coupled to 3-chloro-phenylboronic acid (683 g, 4.4 mmol) acid using Method F to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[CH3:24][C:25]1[O:26][C:27]([CH3:33])=[C:28]([C:30](O)=[O:31])[N:29]=1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:30]([C:28]3[N:29]=[C:25]([CH3:24])[O:26][C:27]=3[CH3:33])=[O:31])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: Cc1nc(C(=O)O)c(C)o1
Product: Cc1nc(C(=O)NC[C@@H]2C[C@@H]3C[C@@H]3N2C(=O)c2nc(N)sc2-c2cccc(F)c2)c(C)o1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 2,5-dimethyl-oxazole-4-carboxylic acid. LC-MS (basic): tR=0.78 min; [M+H]+=456.1.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9](OC)=[CH:8][C:3]=1C(OC)=O.Cl[C:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:17][C:16]=1[C:26]([O:28][CH3:29])=[O:27]>>[C:2]1([C:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:17][C:16]=2[C:26]([O:28][CH3:29])=[O:27])[CH:11]=[CH:10][CH:9]=[CH:8][CH:3]=1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1Cl
Reactant: COC(=O)c1cc(OC)ccc1Br
Product: COC(=O)c1sc(-c2ccccc2)cc1-c1ccccc1
Yield: 90 %

Procedure:
The procedure was followed as outlined in Scheme 2, Step 1 replacing compounds 8 and 9 with compounds 83 and 84 to afford methyl 3,5-diphenylthiophene-2-carboxylate 85 (90% yield) as a white solid after purification by ISCO (12 g column, 0 to 30% ethyl acetate in hexane). LRMS (ESI): (calc) 294.37 (found) 295.21 (MH)+
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([C:9]#[C:10][CH:11]=[C:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:6]=[N:7][CH:8]=1)#N.BrC1C(C#N)=CC=[N:28][CH:27]=1>>[C:27]([C:8]1[N:7]=[CH:6][C:5]([C:9]#[C:10][CH:11]=[C:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:16][CH2:17]2)=[CH:4][CH:3]=1)#[N:28]
Reactant: CC(C)(C)OC(=O)N1CCC(=CC#Cc2cncc(C#N)c2)CC1
Reactant: N#Cc1ccncc1Br
Product: CC(C)(C)OC(=O)N1CCC(=CC#Cc2ccc(C#N)nc2)CC1

Procedure:
The title compound was prepared following the procedure described for the compound of Example 45, but substituting 5-bromo-2-pyridincarbonitrile for 5-bromoisonicotinonitrile. Purification by flash chromatography (EtOAc—Petroleum Ether gradient from 5:95 to 40:60) afforded the title product.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[C:13]1[C:21]2[C:16](=[C:17]([O:22][CH3:23])[N:18]=[CH:19][CH:20]=2)[N:15]([CH3:24])[CH:14]=1.C([BH3-])#N.[Na+].[N:34]1([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(O)(=O)C>CO.ClCCl>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][N:37]2[CH2:38][CH2:39][N:34]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35][CH2:36]2)=[CH:7][C:6]=1[C:13]1[C:21]2[C:16](=[C:17]([O:22][CH3:23])[N:18]=[CH:19][CH:20]=2)[N:15]([CH3:24])[CH:14]=1
Reactant: COc1nccc2c(-c3cc(C=O)ccc3Oc3ccc(F)cc3F)cn(C)c12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: COc1nccc2c(-c3cc(CN4CCN(C(=O)OC(C)(C)C)CC4)ccc3Oc3ccc(F)cc3F)cn(C)c12
Temperature: 75 °C
Yield: 46.5 %

Procedure:
A suspension of Example 105B (100 mg, 0.254 mmol), sodium cyanoborohydride (47.8 mg, 0.761 mmol) and tert-butyl piperazine-1-carboxylate (94 mg, 0.51 mmol) in a mixture of methanol (3 mL), acetic acid (0.073 mL, 1.3 mmol), and dichloromethane (1 mL) was heated at 75° C. 2 hours. Upon cooling, the reaction mixture was partitioned between 50% saturated sodium bicarbonate solution (50 mL) and ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-3% methanol in dichloromethane) to provide the title compound (66.7 mg, 47% yield).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.CC([O-])=O.[Na+].[N:29]#[C:30]Br.O>CO>[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][N:13]([C:30]#[N:29])[CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C#N)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a solution of COMPOUND 249 (0.5021 g, 1.6 mmol) and anhydrous NaOAc (0.3775 g, 4.6 mmol) in MeOH (16 mL) was added at 0° C. cyanogen bromide (0.2315 g, 2.2 mmol), and stirred at for 2 hours at 0° C., then for another 3 hours at room temperature. Distilled water (20 mL) was added and extracted with CH2Cl2 (3×150 mL). The combined organic extracts were washed with brine (2×75 mL), dried (Na2SO4), filtered, and concentrated to provide 0.5137 g (96%) of 4-[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carbonitrile as a beige solid. 1H NMR (CDCl3) δ 1.77-1.90 (m, 2H), 1.95-1.99 (m, 2H), 2.11 (s, 6H), 2.66 (t, 1H, J=12.0 Hz), 2.88-2.97 (m, 2H), 3.45-3.49 (m, 2H), 3.87 (s, 4H), 7.09-7.13 (m, 2H), 7.39 (d, 2H, J=6.0 Hz), 8.36 (d, 2H, J=3.0 Hz).