Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:20]3[CH:19]=[CH:18][C:17]4[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=4[C:15]=3[C:14]3[C:13]4[CH:25]=[CH:26][CH:27]=[CH:28][C:12]=4[CH:11]=[CH:10][C:9]2=3)=[CH:4][CH:3]=1.[C:29]1([C:35]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42](B(O)O)=[C:41]3[C:36]=2[CH:37]=[CH:38][CH:39]=[CH:40]3)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[C:29]1([C:35]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42]([C:2]3[CH:7]=[CH:6][C:5]([N:8]4[C:9]5[CH:10]=[CH:11][C:12]6[CH:28]=[CH:27][CH:26]=[CH:25][C:13]=6[C:14]=5[C:15]5[C:16]6[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=6[CH:18]=[CH:19][C:20]4=5)=[CH:4][CH:3]=3)=[C:41]3[C:36]=2[CH:37]=[CH:38][CH:39]=[CH:40]3)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Brc1ccc(-n2c3ccc4ccccc4c3c3c4ccccc4ccc32)cc1
Reactant: OB(O)c1c2ccccc2c(-c2ccccc2)c2ccccc12
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: Cc1ccccc1
Solvent: CCO
Product: c1ccc(-c2c3ccccc3c(-c3ccc(-n4c5ccc6ccccc6c5c5c6ccccc6ccc54)cc3)c3ccccc23)cc1
Yield: 54.6 %

Procedure:
In a 200 mL three-neck flask were placed 1.7 g (4.0 mmol) of 7-(4-bromophenyl)-7H-dibenzo[c,g]carbazole and 1.2 g (4.0 mmol) of 10-phenylanthracene-9-boronic acid, and the air in the flask was replaced with nitrogen. To this mixture were added 15 mL of toluene, 5.0 mL of ethanol, and 4.0 mL of an aqueous solution of sodium carbonate. This mixture was degassed by being stirred while the pressure was reduced. To this mixture was added 0.23 g (0.20 mmol) of tetrakis(triphenylphosphine)palladium(0), and the mixture was stirred at 90° C. for 10 hours under a nitrogen stream, so that a solid was precipitated. The precipitated solid was removed by suction filtration. The collected solid was dissolved in about 50 mL of hot toluene, and this solution was suction-filtered through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), alumina, and Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135). A solid obtained by concentration of the filtrate was washed with toluene/hexane to give 1.3 g of a pale yellow powder, which was the object of the synthesis, in a yield of 55%. A synthesis scheme (d-2) of Step 4 is illustrated below.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[OH:13][C:11]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:4][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: Nc1ccccc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1cnc2ccccc2c1O
Temperature: 200 °C
Reaction time: 2 h
Yield: 44.1 %

Procedure:
Diethyl ethoxymethylenemalonate (115 g) was dropwise added to aniline (50 g), and the mixture was refluxed for 1 hr. The resulting ethanol was evaporated under atmospheric pressure, and the residue was heated at 200° C. and poured into diphenyl ether (750 mL). The mixture was stirred at 220-250° C. for 2 hr with heating. The resulting ethanol was again evaporated under atmospheric pressure, and the reaction mixture was allowed to cool to room temperature. The precipitated solid was collected by filtration and washed with hexane to give ethyl 4-hydroxyquinoline-3-carboxylate (51.0 g) as a white powder.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:15]#[N:16])=[C:8]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:17]([N:36]1[C:40]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:47]2[CH:54]=[CH:53][C:50]([CH2:51]Br)=[CH:49][CH:48]=2)=[N:39][N:38]=[N:37]1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC(C)([O-])C.[K+]>>[CH2:1]([C:5]1[N:6]([CH2:51][C:50]2[CH:49]=[CH:48][C:47]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[C:40]3[N:36]([C:17]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:37]=[N:38][N:39]=3)=[CH:54][CH:53]=2)[C:7]([C:15]#[N:16])=[C:8]([C:10](=[O:14])[CH:11]([CH3:12])[CH3:13])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C(=O)C(C)C)c(C#N)[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCCc1nc(C(=O)C(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
Following a procedure similar to that described in Example 74(a), but using 1.42 g of 2-butyl-4-isobutyrylimidazole-5-carbonitrile (prepared as described in Preparation 27) 4.49 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide and 0.76 g of potassium t-butoxide. 3.04 g of the title compound was obtained as crystals, melting at 115°-116° C.
Reaction SMILES: [CH2:1]([S:4]([O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)(=[O:6])=[O:5])[CH:2]=C.[Cl:15]Cl.[CH:17]([Cl:20])(Cl)Cl>>[Cl:15][CH:2]([CH2:17][Cl:20])[CH2:1][S:4]([O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)(=[O:6])=[O:5]
Reactant: C=CCS(=O)(=O)Oc1ccc(Cl)cc1
Reactant: ClCl
Reactant: ClC(Cl)Cl
Product: O=S(=O)(CC(Cl)CCl)Oc1ccc(Cl)cc1
Yield: 84.2 %

Procedure:
To a solution of 23.2 g of 4-chlorophenyl 2-propenesulfonate in 80 ml of chloroform was added 7.1 g of chlorine absorbed in 20 ml of chloroform dropwise with stirring below 0°C. After the addition, the mixture was stirred for two hours at room temperature. By distillation of the solvent and fractionation, 25.5 g of 4-chlorophenyl 2,3-dichloropropanesulfonate, B.P. 143°-145°C/0.015 mmHg, was obtained in a yield of 84.2%.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH2:12][O:13][C:14](=[O:24])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)=[O:9])=[CH:4][CH:3]=1.Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl.[O:39]1CCOC[CH2:40]1>>[N:23]([C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][C:14]([O:13][CH2:12][CH2:11][O:10][C:8](=[O:9])[CH2:7][O:6][C:5]2[CH:25]=[CH:26][C:2]([N:1]=[C:40]=[O:39])=[CH:3][CH:4]=2)=[O:24])=[CH:22][CH:21]=1)=[C:28]=[O:30]
Reactant: Nc1ccc(OCC(=O)OCCOC(=O)COc2ccc(N)cc2)cc1
Reactant: C1COCCO1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: O=C=Nc1ccc(OCC(=O)OCCOC(=O)COc2ccc(N=C=O)cc2)cc1
Temperature: 77.5 °C
Yield: 44.2 %

Procedure:
(4-Aminophenoxy)acetic acid 2-[2-(4-aminophenoxy)acetoxy]ethyl ester 43 (5 g, 14.3 mmol) was dissolved in dry dioxane (80 ml) under nitrogen atm. and cooled to below 20° C. A solution of triphosgene (7 g, 23.6 mmol) in dry dioxane (20 ml) was added drop wise. The mixture was heated slowly to 75-80° C. and maintained for 2½ hours. The condenser was then arranged for distillation and solvent removed by distillation at atmospheric pressure until the volume of the reaction mixture was reduced to approximately one third. Fresh dry dioxane (50 ml) was added and the solvents were distilled off under vacuum. The residue was re-evaporated two times from dry dioxane to give crude 44. Crude 44 was recrystallised from a mixture of toluene:hexane (1:3) to give pure 44 (2.6 g, 44.2%) as a white powder. M.p: 96-98° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([C:23]([F:26])([F:25])[F:24])[CH:15]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[Cl:34]CCl>>[ClH:34].[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([NH:13][C@@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)=[CH:15][C:16]=1[C:23]([F:26])([F:24])[F:25])([O-:22])=[O:21]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=[N+]([O-])c1ccc(N[C@@H]2CCNC2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To solid (R)-3-(4-Nitro-3-trifluoromethyl-phenylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.12 g; 2.98 mmol, prepared in accordance with Example 164) is added a 3:2 mixture of dichloromethane and trifluoroacetic acid (5 mL) and the resulting solution is stirred at room temperature for 2 hours. All volatiles are then removed under high vacuum and the residue taken up in ethyl acetate. A 4 molar solution of hydrochloric acid in dioxane is then added and, after formation of an oily precipitate, all volatiles removed under high vacuum. The obtained residue is then taken up in methanol and treated with diethyl ether. This mixture is allowed to stand over night, concentrated under high vacuum and taken up in hot ethyl acetate. The solution is then allowed to stand at room temperature over night and the precipitate formed is collected and dried under high vacuum to afford the desired compound (1.07 g) which is used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:7]3[C:12]([S:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[CH:22]1[CH:27]=[C:26]([CH:28]=O)[N:25]=[CH:24][CH:23]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:16]3[CH2:21][CH2:20][N:19]([CH2:28][C:26]4[CH:27]=[CH:22][CH:23]=[CH:24][N:25]=4)[CH2:18][CH2:17]3)[C:7]3[C:12]([S:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: O=Cc1ccccn1
Reactant: Brc1ccc2c(c1)Sc1ccccc1N2C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: Brc1ccc2c(c1)Sc1ccccc1N2C1CCN(Cc2ccccn2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-bromo-10-piperidin-4-yl-10H-phenothiazine, 5e (10.5 mg; 0.029 mmol) and 2-pyridyl carboxaldehyde (9.3 mg; 0.087 mmol) in dichloroethane (120 μL) was added acetic acid (5 μL) and a solution of sodium triacetoxyborohydride (12 mg, 0.057 mmol) in DMF (100 μL). The mixture was stirred at rt for 18 h, quenched with water (50 μL), and lyophilized. The thus obtained crude 3-bromo-10-(1-pyridin-2-ylmethyl-piperidin-4-yl)-10H-phenothiazine, 1f was used as such for the next reaction.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[C:13]([NH2:15])[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][CH:10]=1.[H-].[Na+].[C:23]([C:27]1[CH:28]=[C:29]([C:33](Cl)=[O:34])[N:30]([CH3:32])[N:31]=1)([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[C:23]([C:27]1[CH:28]=[C:29]([C:33]([N:15]([C:13]2[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:1])([F:19])[F:20])[N:14]=2)[C:33]([C:29]2[N:30]([CH3:32])[N:31]=[C:27]([C:23]([CH3:25])([CH3:24])[CH3:26])[CH:28]=2)=[O:34])=[O:34])[N:30]([CH3:32])[N:31]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: Cn1nc(C(C)(C)C)cc1C(=O)Cl
Reactant: Nc1nc(-c2ccccc2C(F)(F)F)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1nc(C(C)(C)C)cc1C(=O)N(C(=O)c1cc(C(C)(C)C)nn1C)c1nc(-c2ccccc2C(F)(F)F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine (200 mg, 0.706 mmol, prepared as described in Example 22, STEP B) in THF (15 mL) was treated with NaH (84.7 mg, 2.12 mmol) at room temperature for 1 h. The resulting mixture was treated with a solution of 5-tert-butyl-2-methyl-2H-pyrazole-3-carbonyl chloride (156 mg, 0.777 mmol) as a solution in THF (6 mL) and allowed to stir at room temperature for 15 min. The mixture was quenched with saturated aqueous NH4Cl (25 mL) and extracted twice with EtOAc (35 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 24-g SEPRA Si 50 SPE column (Isco system: Flow rate=20 mL/min; Eluent=EtOAc/hexanes, 1:99 v/v for 5 min, then 1:99 to 1:9 v/v over 40 min) to yield 5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid (5-tert-butyl-2-methyl-2H-pyrazole-3-carbonyl)-[3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-2-yl]-amide as a yellow solid. Mass Spectrum (LCMS, APCI pos.): Calculated for C30H32F3N7O4: 612.3 (M+H); Measured: 612.1.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12]>Cl>[Cl:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: C1=COCCC1
Reactant: OCCCCCl
Agent: Cl
Product: ClCCCCOC1CCCCO1
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
Dihydropyran (15.5 g) was added dropwise to a mixture of 4-chlorobutanol (20 g) and hydrochloric acid (18M, 1 drop) at RT. The mixture was stirred for 30 min and washed with H2O (100 ml), aqueous NaHCO3 (1M, 50 ml) and BR (50 ml). The dried liquid was heated under reduced pressure to leave the title compound as a colourless liquid (31.9 g). T.l.c. [L] Rf 0.5.
Reaction SMILES: C(OC(N1[C@H](C=CCCCO)COC1(C)C)=O)(C)(C)C.C[Si](C)(C)Br.C([O:28][C:29](=[O:49])[CH:30]([NH:45][C:46](C)=O)/[CH:31]=[C:32](\[CH3:44])/[CH2:33][P:34]([O:40]C(C)C)([O:36]C(C)C)=[O:35])C.C1OC1C>ClCCl.C(O)C>[CH3:46][NH:45][CH:30](/[CH:31]=[C:32](\[CH3:44])/[CH2:33][P:34]([OH:36])([OH:40])=[O:35])[C:29]([OH:49])=[O:28]
Reactant: CCOC(=O)C(/C=C(\C)CP(=O)(OC(C)C)OC(C)C)NC(C)=O
Agent: CC(C)(C)OC(=O)N1[C@H](C=CCCCO)COC1(C)C
Agent: CC1CO1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CCO
Product: CNC(/C=C(\C)CP(=O)(O)O)C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
E-2-methylamino-4-methyl-5-phosphono-3-pentenoic acid (3) 20 ml of trimethylbromosilane are added dropwise at 20° within a period of 10 minutes under argon to a solution of 9.50 g of E-2-(N-methylformylamino)-4-methyl-5-diisopropylphosphono-3-pentenoic acid ethyl ester in 40 ml of dry dichloromethane. After stirring at room temperature for 20 hours, 37 ml of ethanol are added dropwise within a period of 15 minutes, and the who)e is stirred for a further 20 hours. The clear reaction solution is then concentrated to dryness by evaporation in vacuo. The residue is concentrated by evaporation twice more in each case after the addition of 30 ml of toluene. 128 ml of 2 N hydrochloric acid are added to the resulting oil, and the mixture is stirred at a bath temperature of 85° for 16 hours. The reaction mixture is concentrated by evaporation in vacuo. Concentration by evaporation twice after the addition of ethanol/toluene 1:1 yields an oily residue, which is dissolved in 51 ml of ethanol and to which there is added dropwise a solution of 51 ml of propylene oxide in 51 ml of ethanol. The product obtained in crystalline form is filtered off after 2 hours and recrystallised from water/ethanol. In this manner there is obtained E-2-methylamino-4-methyl-5-phosphono-3-pentenoic acid, m.p. 239° (decomp.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([Cl:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[F:23][C:24]1[CH:25]=[N:26][NH:27][C:28]=1[Sn](CCCC)(CCCC)CCCC.C([O-])([O-])=O.[Na+].[Na+]>CS(C)=O.CCOC(C)=O.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>[Cl:18][C:15]([F:17])([F:16])[O:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:19]=[CH:20][C:21]([F:22])=[C:2]([C:28]3[NH:27][N:26]=[CH:25][C:24]=3[F:23])[CH:3]=2)=[CH:9][CH:10]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(F)c(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1[nH]ncc1F
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: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(F)c(-c2[nH]ncc2F)c1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of 3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-fluorobenzamide (Stage 20.2, 200 mg, 0.497 mmol), 4-fluoro-5-(tributylstannyl)-1H-pyrazole (211 mg, 0.472 mmol) and Pd(PPh3)4 (28.7 mg, 0.025 mmol) in DMSO (1.5 mL) in a sealed vial was stirred at 100° C. for 20 h under an argon atmosphere. The RM was diluted with EtOAc (30 mL), treated with sat. aq. Na2CO3 (20 mL) and extracted with EtOAc. The combined extracts were washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product which was purified by flash chromatography (Silica gel column, 12 g, n-hexane/EtOAc 95:5 to 6:4) to give the title product as a white solid. HPLC (Condition 5) tR=7.20 min, UPLC-MS (Condition 3) tR=1.12 min, m/z=400.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[NH:12][C:11]([C:14]3[C:15](=[O:21])[NH:16][CH:17]=[CH:18][C:19]=3Cl)=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[Cl:22][C:23]1[CH:24]=[C:25]([CH2:29][CH2:30][NH2:31])[CH:26]=[CH:27][CH:28]=1.C(N(CC)CC)C.COC(C1C2NC(C3C(=O)NC=CC=3NC[C@@H](O)C3C=CC=CC=3)=NC=2C=CC=1)=O>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[C:13]2[NH:12][C:11]([C:14]3[C:15](=[O:21])[NH:16][CH:17]=[CH:18][C:19]=3[NH:31][CH2:30][CH2:29][C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([Cl:22])[CH:24]=3)=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: NCCc1cccc(Cl)c1
Reactant: COC(=O)c1cccc2nc(-c3c(Cl)cc[nH]c3=O)[nH]c12
Agent: COC(=O)c1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1cccc2nc(-c3c(NCCc4cccc(Cl)c4)cc[nH]c3=O)[nH]c12

Procedure:
2-{4-[2-(3-Chloro-phenyl)-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-3H-benzoimidazole-4-carboxylic acid methyl ester was synthesized from 2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-3H-benzoimidazole-4-carboxylic acid methyl ester, 2-(3-Chloro-phenyl)-ethylamine, triethylamine, and ACN using a similar procedure as 2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazole-4-carboxylic acid methyl ester yielding 2-{4-[2-(3-chloro-phenyl)-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-3H-benzoimidazole-4-carboxylic acid methyl ester.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:20]([CH2:23]OC)OC.[H-].[Na+].C(I)C>CN(C)C=O.C(O)(C)C>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([O:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH2:20][CH3:23])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(OCCc2ccccc2O)CC1
Reactant: COCCOC
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCI
Solvent: CN(C)C=O
Product: CCOc1ccccc1CCOC1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 536.1 %

Procedure:
N-Acetyl-4-(2-hydroxyphenethyloxy)piperidine (8.0 g.) and dimethoxyethane (0.3 g.) in dry dimethylformamide (50 ml.) were added dropwise to a stirred suspension of sodium hydride (2.96 g., 50% dispersion in mineral oil) in dry dimethylformamide (50 ml.). The suspension was stirred at room temperature for 3.5 hours, cooled to 0°-5° C. then a solution of ethyl iodide (9.6 g.) in dimethylformamide (25 ml.) added dropwise. The mixture was allowed to warm to room temperature (20° C.), then stirred at room temperature for 2 hours. Isopropanol (75 ml.) was added, the solvent removed in vacuo and the residue partitioned between chloroform and water. The chloroform layer was dried and the solvent evaporated in vacuo to give N-acetyl-4-(2-ethoxyphenethyloxy)piperidine (5.2 g.).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[CH2:28]([NH:35][CH2:36][CH2:37][OH:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:35]([CH2:36][CH2:37][OH:38])[C:23]([C:22]1[CH:21]=[CH:20][C:19]([C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:6]3[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH2:12][CH2:13]2)=[O:18])=[CH:27][CH:26]=1)=[O:25])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Reactant: OCCNCc1ccccc1
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N(CCO)Cc3ccccc3)cc2)CC1
Yield: 81 %

Procedure:
By the same procedure as described in the example 1, synthesis was carried out starting with 4-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid and using 2-(benzylamino)ethanol. Then, the product was recrystallized using isopropanol and isopropyl ether, filtered and dried to give the desired compound.
Reaction SMILES: C[Al](C)C.[NH2:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([N:12]([CH3:14])[CH3:13])=[O:11])=[CH:8][N:7]=1.[Cl:17][C:18]1[C:19]([N:24]2[C:28]3=[N:29][CH:30]=[N:31][C:32]([O:33][C@@H:34]([CH2:39][O:40][CH:41]([CH3:43])[CH3:42])[C:35](OC)=[O:36])=[C:27]3[CH:26]=[N:25]2)=[N:20][CH:21]=[CH:22][CH:23]=1.CCCCCC>C1(C)C=CC=CC=1>[Cl:17][C:18]1[C:19]([N:24]2[C:28]3=[N:29][CH:30]=[N:31][C:32]([O:33][C@@H:34]([CH2:39][O:40][CH:41]([CH3:43])[CH3:42])[C:35]([NH:5][C:6]4[CH:16]=[CH:15][C:9]([C:10]([N:12]([CH3:14])[CH3:13])=[O:11])=[CH:8][N:7]=4)=[O:36])=[C:27]3[CH:26]=[N:25]2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: CN(C)C(=O)c1ccc(N)nc1
Reactant: COC(=O)[C@H](COC(C)C)Oc1ncnc2c1cnn2-c1ncccc1Cl
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)OC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(C(=O)N(C)C)cn1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Trimethylaluminium (2M in hexane, 0.376 mL, 0.75 mmol) was added to 6-amino-N,N-dimethylnicotinamide (CAS no. 827588-33-0) (108 mg, 0.65 mmol) in toluene (20 mL) at 0° C. under Nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (2S)-Methyl 2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-isopropoxypropanoate (Intermediate L1) (256 mg, 0.65 mmol) in toluene (6 mL) was added dropwise at this temperature. After the addition was complete, the solution was allowed to warm to ambient temperature and was then heated to reflux for 16 hours. Allowed to cool to ambient temperature. The reaction mixture was concentrated and diluted with EtOAc (100 mL) and washed with saturated brine (50 mL). The organic layer was dried (MgSO4), filtered and evaporated. 2M Trimethylaluminium in hexane (0.376 mL, 0.75 mmol) was added to 6-amino-N,N-dimethylnicotinamide (108 mg, 0.65 mmol) in toluene (20 mL) at 0° C. under Nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. The residue from the above evaporation was dissolved in toluene (6 mL) and added dropwise. After the addition was complete, the solution was allowed to warm to ambient temperature and was then heated to reflux for 16 hours. Allowed to cool to ambient temperature. The reaction mixture was concentrated and diluted with EtOAc (100 mL) and washed with saturated brine (50 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl[CH2:19][CH2:20][OH:21].[CH2:22]([OH:24])[CH3:23]>>[OH:21][CH2:20][CH2:19][S:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH2:23][CH2:22][OH:24])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: OCCCl
Reactant: CCO
Reactant: Sc1ccc(-c2ccc(S)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCCSc1ccc(-c2ccc(SCCO)cc2)cc1

Procedure:
A mixture of 4,4'-dimercaptobiphenyl (41.7 grams, 0.19 mole), 50% NaOH [31.2 grams (15.6 grams, 0.39 mole NaOH)], water (100 mL) and 2 β ethanol (60 mL) was heated under nitrogen under stirring while 2-chloroethanol (31.5 grams, 0.39 mole) was added dropwise at reflux. When addition was completed, additional 2 β ethanol (60 mL) was added to facilitate stirring. After being heated an additional 2.0 hours at reflux, the reaction mixture was allowed to cool and the product was collected by vacuum filtration, washed with water and dried in air.