Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[C:12]2[N:13]=[C:14]([NH:27][C:28]3[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=3)[N:15]=[C:16]([NH:17][C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=3[CH3:26])[C:11]=2[CH:10]=[CH:9]1)C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1Cl>[CH3:26][C:19]1[CH:20]=[C:21]([CH3:25])[CH:22]=[C:23]([CH3:24])[C:18]=1[NH:17][C:16]1[C:11]2[CH:10]=[CH:9][NH:8][C:12]=2[N:13]=[C:14]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([C:32]#[N:33])=[CH:34][CH:35]=2)[N:15]=1
Reactant: Cc1cc(C)c(Nc2nc(Nc3ccc(C#N)cc3)nc3c2ccn3Cc2ccccc2)c(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: Cc1cc(C)c(Nc2nc(Nc3ccc(C#N)cc3)nc3[nH]ccc23)c(C)c1
Temperature: 160 °C
Reaction time: 2 h
Yield: 18.3 %

Procedure:
To a solution of 4-[7-benzyl-4-(2,4,6-trimethyl-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-benzonitrile (34 mg, 0.074 mmol) in 1,2-dichlorobenzene (1 mL) was added aluminum chloride (50 mg, 0.37 mmol). The reaction mixture was stirred at 160° C. for 2 h and cooled to room temperature. The mixture was poured into ice water and extracted with CHCl3 (2×10 mL). The combined organic solution was washed with brine (10 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (CH2Cl2:Acetone=90:10) yielded 5 mg (19%) of 4-[4-(2,4,6-trimethyl-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-benzonitrile as a tan solid.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[CH:5]1[C:10]([NH2:11])=[CH:9][CH:8]=[C:7](N)[CH:6]=1>O>[CH:9]1[C:10]([NH2:11])=[CH:5][CH:6]=[C:7]([NH:1][C:2]([NH:4][C:7]2[CH:8]=[CH:9][C:10]([NH2:11])=[CH:5][CH:6]=2)=[O:3])[CH:8]=1
Reactant: Nc1ccc(N)cc1
Reactant: NC(N)=O
Solvent: O
Product: Nc1ccc(NC(=O)Nc2ccc(N)cc2)cc1

Procedure:
To a 1-liter, 3-neck round-bottom flask equipped with a mechanical stirrer, nitrogen inlet tube extending below the liquid level and a reflux condenser with a nitrogen exit to a gas bubbler, was added 500 ml. of distilled water. After the water was de-oxygenated by bubbling nitrogen gas through it for 3 hours, 15 g. (0.25 mole) of a commercial pre-dried urea and 60 g. (0.554 mole) of purified p-phenylenediamine were added and the solution which formed was refluxed for about 72 hours under a nitrogen atmosphere. The diamine to urea mole ratio utilized was 2.22.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[N:28][C:29]([O:32]C)=[CH:30][CH:31]=2)=[CH:22][CH:21]=1)[CH3:19])[C:10]([N:12]1[CH2:16][CH2:15][C@H:14]([F:17])[CH2:13]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.N1C=CC=CC=1.C(=O)(O)[O-].[Na+].C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>O1CCOCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29](=[O:32])[NH:28][CH:27]=2)=[CH:22][CH:21]=1)[CH3:19])[C:10]([N:12]1[CH2:16][CH2:15][C@H:14]([F:17])[CH2:13]1)=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(-c2ccc([C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N3CC[C@H](F)C3)cc2)cn1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: C[C@@H](c1ccc(-c2ccc(=O)[nH]c2)cc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Temperature: 160 °C
Reaction time: 0.33 h

Procedure:
(3S)-1-[(2S,3S)-2-(tert-Butoxycarbonylamino)-3-[4-(6-methoxypyridin-3-yl)phenyl]-1-oxobutanyl]-3-fluoropyrrolidine from Example 5, Step A (0.65 g, 1.42 mmol) was mixed with pyridine hydrochloride (2.25 g, 19.5 mmol) neat and placed in a preheated oil bath (160° C.). After stirring at 160° C. for 20 min, the reaction was cooled to room temperature and neutralized to pH 7 with saturated sodium bicarbonate solution. To this was added 15 mL of 1,4-dioxane followed by di-tert-butyldicarbonate (2.14 g, 9.82 mmol). After stirring at room temperature for 12 h, the reaction was partitioned between ethyl acetate and saturated aqueous brine. The organic layer was separated, and the aqueous layer was extracted with two portions of ethyl acetate. The combined organic layers were dried over sodium sulfate and the solvents removed by evaporation under diminished pressure. Purification by preparative TLC (silica, 50% ethyl acetate/hexanes) afforded the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:11]=[C:10](Cl)[CH:9]=[C:8]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=2)[CH:7]=1.C([O-])=O.[Na+]>[Pd].C(O)(C)C>[NH2:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[O:13][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([O:5][C:4]2[CH:21]=[CH:22][CH:23]=[C:2]([NH2:1])[CH:3]=2)[CH:7]=1
Reactant: Nc1cccc(Oc2cc(Cl)cc(Oc3cccc(N)c3)c2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: Nc1cccc(Oc2cccc(Oc3cccc(N)c3)c2)c1
Reaction time: 5 h
Yield: 90.3 %

Procedure:
Into a glass vessel equipped with a thermometer, a reflux condenser and a stirrer were fed 1,3-bis(3-aminophenoxy)-5-chlorobenzene (8.2 g, 0.025 mol), 5% Pd-C (made by Japan Engelhardt Co.) (0.25 g), sodium formate (4.3 g, 0.063 mol) and 60% aqueous solution of isopropanol (50 ml), and reaction was carried out under reflux with stirring for 5 hours. After completion of the reaction, the catalyst was removed by filtering while hot, followed by cooling to deposit colorless, prismatic crystals, which were filtered and dried to obtain 1,3-bis(3-aminophenoxy)benzene (6.6 g, yield 90.3%). The purity according to high rate liquid chromatography was 99%. M.P.: 105°~107° C.
Reaction SMILES: S(=O)(=O)=O.[N+:5]([C:8]1[CH:9]=[C:10]([S:15]([O:18]S(C2C(C)=CC=C([N+]([O-])=O)C=2)(=O)=O)(=[O:17])=[O:16])[C:11]([CH3:14])=[CH:12][CH:13]=1)([O-:7])=[O:6]>O>[N+:5]([C:8]1[CH:9]=[C:10]([S:15]([OH:18])(=[O:16])=[O:17])[C:11]([CH3:14])=[CH:12][CH:13]=1)([O-:7])=[O:6]
Reactant: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)OS(=O)(=O)c1cc([N+](=O)[O-])ccc1C
Agent: O=S(=O)=O
Solvent: O
Product: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)O

Procedure:
In this procedure, the reaction mixture is obtained as a black, tarry suspension towards the end of the addition of sulphur trioxide and, after hydrolysis of the p-nitrotoluene-2-sulphonic acid anhydride with water, an aqueous solution of p-nitrotoluene-2-sulphonic acid is formed from the suspension, and this is treated with active charcoal, before or after separating off water-insoluble by-products, in order to separate off dissolved, coloured compounds and dissolved, unreacted p-nitrotoluene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:27])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:18])=[N:6][CH:7]=1.C([BH3-])#N.[Na+].Cl.[CH3:33][C:34]([CH3:36])=O>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:27])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([O:19][CH:20]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:34]([CH3:36])[CH3:33])=[O:18])=[N:6][CH:7]=1
Reactant: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)OCC1CCNCC1
Reactant: CC(C)=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)C(OC(=O)Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)C1CCNCC1

Procedure:
Using a similar procedure to that described in Example 9-C, N-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylmethoxycarbonyl)amino]benzamide (100 mg, 0.199 mmol), acetone (0.075 mL), and sodium cyanoborohydride (50 mg, 0.80 mmol) yielded, after treatment with HCl, 25 mg of the title compound as a hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:37]#[N:38])=[C:6]([C:8]2[C:13]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:12][N:11]([CH:18]([CH3:35])[C:19]([NH:21][C:22]3[CH:34]=[CH:33][C:25]([C:26]([O:28]C(C)(C)C)=[O:27])=[CH:24][CH:23]=3)=[O:20])[C:10](=[O:36])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:37]#[N:38])=[C:6]([C:8]2[C:13]([O:14][CH:15]([CH3:16])[CH3:17])=[CH:12][N:11]([CH:18]([CH3:35])[C:19]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:33][CH:34]=3)=[O:20])[C:10](=[O:36])[CH:9]=2)[CH:7]=1
Reactant: CC(C)Oc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1cn(C(C)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
31 mg (0.06 mmol) of tert-butyl 4-({2-[4-(5-chloro-2-cyanophenyl)-2-oxo-5-(propan-2-yloxy)pyridin-1(2H)-yl]propanoyl}amino)benzoate (racemate) (Example 24.11) were hydrolysed with TFA according to General Method 2. Yield: 5 mg (18% of theory)
Reaction SMILES: [NH2:1][CH:2]([CH2:14][CH3:15])[C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=O.C(OCC)(=O)C.O.[OH-].[Na+]>C(OCC)C>[CH3:12][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:13])[C:6]=1[NH:5][CH2:3][CH:2]([NH2:1])[CH2:14][CH3:15]
Reactant: CCC(N)C(=O)Nc1c(C)cccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(N)CNc1c(C)cccc1C
Reaction time: 3 h
Yield: 40.9 %

Procedure:
2.5 g (66 mmoles) of lithium-aluminium-hydride are added in small portions, at room temperature, to a solution of 3.6 g (17.4 mmoles) of N-(2-aminobutyryl)-2,6-dimethyl-aniline in 40 ml of dry diethyl ether, and the resulting mixture is boiled for 3 hours. The mixture is cooled with ice, and 10 ml of ethyl acetate, 10 ml of water, finally 12 ml of a 5 n aqueous sodium hydroxide solution are added dropwise. The etheral phase is decanted, and the thick, gelly aqueous phase is washed thrice with 25 ml of diethyl ether, each. The etheral solutions are combined, washed thrice with 25 ml of water, each, dried over anhydrous magnesium sulfate, and the solvent is evaporated. The yellow, oily residue is distilled under reduced pressure to obtain 1.37 g of 1-(2,6-dimethylphenyl-amino)-2-amino-butane, b.p.: 122°-124° C./66.7 Pa, and 0.62 g of unreacted starting substance, b.p.: 158°-172° C./66.7 Pa. The product is obtained with a yield of 49%, calculated for the converted starting substance.
Reaction SMILES: C([O:3][C:4](=[O:37])[C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]2[C:22]([CH2:23][N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:21][C:20]3[C:19]([CH3:30])([CH3:29])[CH:18]([O:31]C(=O)C)[CH2:17][C:16]([CH3:36])([CH3:35])[C:15]=3[CH:14]=2)=[CH:7][CH:6]=1)C>[Li+].[OH-].C(O)C>[CH3:29][C:19]1([CH3:30])[CH:18]([OH:31])[CH2:17][C:16]([CH3:35])([CH3:36])[C:15]2[CH:14]=[C:13](/[CH:12]=[CH:11]/[C:8]3[CH:7]=[CH:6][C:5]([C:4]([OH:37])=[O:3])=[CH:10][CH:9]=3)[C:22]([CH2:23][N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:21][C:20]1=2
Reactant: CCOC(=O)c1ccc(/C=C/c2cc3c(cc2Cn2cccn2)C(C)(C)C(OC(C)=O)CC3(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CC(O)C(C)(C)c2cc(Cn3cccn3)c(/C=C/c3ccc(C(=O)O)cc3)cc21
Temperature: 25 °C
Yield: 79.8 %

Procedure:
A mixture of 0.32 g (0.64 mmol) of ethyl-4-[(E)-2-(5,5,8,8-tetramethyl-3pyrazol-1-ylmethyl-6-acetoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoate in 10 mL of 1 N LiOH solution and 20 mL of ethyl alcohol was heated to reflux. After 1 hour the reaction was cooled to room temperature, concentrated under reduced pressure and acidified with 2 N HCl. The aqueous solution was extracted with ethyl acetate, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to afford 0.22 g (82%) of 4-[(E)-2-(5,5,8,8-tetramethyl-3pyrazol-1-ylmethyl-6-hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoic acid 55 (mp=241.6-242.0°).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[N:11][CH:12]=1.[O:14]=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1>CCOCC>[Cl:13][C:10]1[N:11]=[CH:12][C:7]([C:15]2([OH:14])[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20]2)=[CH:8][CH:9]=1
Reactant: Clc1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)nc2)CC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 51.2 %

Procedure:
n-Butyl lithium (1.6M in hexanes, 6.50 mL, 10.39 mmol) was added dropwise to 5-bromo-2-chloropyridine (2.0 g, 10.39 mmol) in ether (30 mL) cooled to −78° C. over a period of 15 minutes. The resulting solution was stirred at −78° C. for 45 minutes then a solution of tert-butyl 4-oxo-1-piperidinecarboxylate (1.66 g, 8.31 mmol) in ether (10 mL) was added dropwise. The reaction was allowed to warm slowly to room temperature then quenched with ammonium chloride solution (50 mL) and extracted with EtOAc. The extract was washed sequentially with water and saturated brine, dried over MgSO4 and concentrated by evaporation, then purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 4-(6-chloropyridin-3-yl)-4-hydroxypiperidine-1-carboxylate (1.33 g, 41%) as a cream solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:20])=[CH:4][C:5]2[N:9]=[C:8]3[S:10][CH:11]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)[CH2:12][N:7]3[C:6]=2[CH:19]=1.ClC1C=C(C=CC=1)C(OO)=[O:26]>>[CH3:1][C:2]1[C:3]([CH3:20])=[CH:4][C:5]2[N:9]=[C:8]3[S:10](=[O:26])[CH:11]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)[CH2:12][N:7]3[C:6]=2[CH:19]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc2nc3n(c2cc1C)CC(c1ccccn1)S3
Product: Cc1cc2nc3n(c2cc1C)CC(c1ccccn1)S3=O

Procedure:
In a manner analogous to Example 10 2,3-Dihydro-6,7-dimethyl-2-(2-pyridyl)thiazolo- [3,2-a]benzimidazole (2.63 g) was reacted with m-chloroperoxybenzoic acid (1.45 g) to give the title compound as the 1/4 hydrate, mp 177°-8° C. decomp.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8](O/C(/C(OCC)=O)=C\C2C=CC=CC=2F)[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2].[F:39][C:40]([F:56])([F:55])[C:41]1[CH:42]=[C:43]([CH2:47][C:48](=[O:54])[C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH:44]=[CH:45][CH:46]=1.[H-].[Na+].[Br-].C(O[C@@H]1[C@@H](OC(=O)C)[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@@H]1O)(=O)C>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:54]/[C:48](/[C:49]([O:51][CH2:52][CH3:53])=[O:50])=[CH:47]\[C:43]2[CH:44]=[CH:45][CH:46]=[C:41]([C:40]([F:55])([F:56])[F:39])[CH:42]=2)[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=O)Cc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)/C(=C/c1ccccc1F)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Br-]
Agent: [H-]
Product: CCOC(=O)/C(=C/c1cccc(C(F)(F)F)c1)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 22 %

Procedure:
The title compound was prepared as described for C4 using ethyl 3-(3-(trifluoromethyl)phenyl)-2-oxopropanoate B10 (100 mg, 0.384 mmol), sodium hydride (10.14 mg, 0.544 mmol) and 2,3,4,6-tetra-O-acetyl-α-D-glucose bromide (158 mg, 0.384 mmol). The resulting compound was isolated in the form of white solid in 22% yield.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].Cl.[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41](Cl)=[O:42]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:41]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=3)=[O:42])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccccn4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 55.1 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.98 g, 6.48 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.60 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, picolinoyl chloride hydrochloride (0.41 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 mL). The CH2Cl2 solution was washed with 1N HCL (30 mL), H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2: CH3OH 97.5:2.5) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}-2-pyridylcarboxamide (0.40 g, 55%) as a white solid: mp 155-157° C.; 1H NMR (DMSO-d6) δ 11.15 (s, 1H), 9.50 (t, J=6.2 Hz, 1H), 8.70 (d, J=4.6 Hz, 1H), 8.08-7.98 (m, 2H), 7.82-7.62 (m, 4H), 5.21-5.14 (dd, J=5.4 and 12.6 Hz, 1H), 4.97 (d, J=6.3 Hz, 2H), 2.99-2.84 (m, 1H), 2.65-2.50 (m, 2H), 2.10-2.06 (m, 1H); 13C NMR (DMSO-d6) δ 172.77, 169.85, 167.59, 166.99, 164.38, 149.59, 148.56, 139.02, 137.87, 134.79, 132.95, 131.57, 127.16, 126.76, 122.05, 121.87, 48.87, 38.37, 30.94, 21.97; Anal. Calcd. For C20H16N4O5+0.08H2O: C, 61.08; H, 4.13; N, 14.25. Found: C, 61.48; H, 4.22; N, 13.87.
Reaction SMILES: [S:1]1[C:5]([CH2:6][CH2:7][C:8]([OH:10])=O)=[CH:4][C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]1=2.CCN(CC)CC.C(Cl)(=O)C(C)(C)C.O1CCNC1=O.[Li]CCCC.[CH2:40]([C@H:47]1[CH2:51][O:50][C:49](=[O:52])[NH:48]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1.C(Cl)(Cl)Cl>[S:1]1[C:5]([CH2:6][CH2:7][C:8]([N:48]2[C@@H:47]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:51][O:50][C:49]2=[O:52])=[O:10])=[CH:4][C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]1=2
Reactant: O=C(O)CCc1cc2ccccc2s1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: O=C1NCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(CCc1cc2ccccc2s1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
To a solution of benzo[b]thiophene-2-propanoic acid (1.10 g, 5.33 mmol) and Et3N (0.89 mL, 6.4 mmol) in dry THF (22 mL) at -78° C. was added dropwise pivaloyl chloride (0.66 mL, 5.4 mmol). After the resultant white suspension was stirred for 10 min at -78° C. and 30 min at 0° C., it was recooled to -78° C. and a precooled (-78° C.) solution of metallated oxazolidinone, prepared by addition of n-BuLi (1.6M in hexane, 3.66 mL, 5.85 mmol) to a -78° C. solution of (S)-(-)-4-benzyl-2-oxazolidinone (1.05 g, 5.87 mmol) in THF (22 mL), was added via a cannula. The reaction mixture was stirred for an additional 1 h and then was quenched by addition of saturated aq. NH4Cl (36 mL). The mixture was concentrated and the residue was extracted with CH2Cl2 (3×100 mL). The combined organic phases were washed with saturated aq. NaHCO3 (85 mL), dried (Na2SO4) and concentrated to dryness. The crude solid (2.31 g) was purified by flash chromatography, eluting with EtOAc-hexane (1:2.5) to give (S)-3-[3-(benzo[b]thien-2-yl)-1-oxopropyl]-4-(phenylmethyl)-2-oxazolidinone (1.82 g, 4.98 mmol) in 93% yield as a solid, mp 119°-122° C. [α]25D +54.9° (c 0.55, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)[C:6](=[O:19])[N:5]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:4]=2[N:3]=1.O[NH:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)=[NH:28]>CN(C=O)C>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[O:18][N:28]=[C:27]([C:29]4[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=4)[N:26]=3)[C:6](=[O:19])[N:5]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:4]=2[N:3]=1
Reactant: CCCCCn1c(=O)n(CCCCC(=O)O)c(=O)c2[nH]c(Cl)nc21
Reactant: N=C(NO)c1ccc(O)cc1
Solvent: CN(C)C=O
Product: CCCCCn1c(=O)n(CCCCc2nc(-c3ccc(O)cc3)no2)c(=O)c2[nH]c(Cl)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoic acid (50 mg, 0.14 mmol) in DMF (2 ml) was treated with CDl (23 mg, 0.14 mmol) and stirred at rt for 30 min. N,4-dihydroxybenzenecarboximidamide (26 mg, 0.17 mmol) was added and the mixture heated in the microwave at 120° C. for 15 min. After cooling the reaction was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, concentrated and purified by the MDAP. The title compound was obtained as an off-white solid (17 mg, 26%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]3[N:23]([CH2:24][CH2:25][CH2:26][O:27][CH3:28])[C:22]4[CH:29]=[CH:30][CH:31]=[C:32]([Cl:33])[C:21]=4[N:20]=3)[CH2:14]2)=[O:12])=[CH:4][CH:3]=1.[C:42]1(B(O)O)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:2]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]3[N:23]([CH2:24][CH2:25][CH2:26][O:27][CH3:28])[C:22]4[CH:29]=[CH:30][CH:31]=[C:32]([Cl:33])[C:21]=4[N:20]=3)[CH2:14]2)=[O:12])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc(Br)cc3)NC(=O)OC(C)(C)C)C2)nc2c(Cl)cccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc(-c4ccccc4)cc3)NC(=O)OC(C)(C)C)C2)nc2c(Cl)cccc21
Temperature: 110 °C

Procedure:
tert-Butyl (R)-1-(4-bromophenyl)-4-((R)-3-(4-chloro-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate (48B) (0.245 mmol, crude oil) and phenylboronic acid (0.294 mmol, 0.036 g) were added to a 5 mL microwave vessel equipped with a magnetic stir bar. Dioxane (2 mL) and Na2CO3 (1 mL of a 2M in aq. soln.) were then added and the reaction vessel was flushed with nitrogen gas. PdCl2(dppf) (0.025 mmol, 0.018 g) was added, the reaction vessel was sealed and placed in a microwave reactor and heated to 110° C. for 15 minutes. The reaction solution was then poured into water, extracted with ethyl acetate, and washed once with saturated aqueous sodium chloride. The organic layer was collected and subsequently dried with anhydrous Na2SO4 and filtered. This filtrate was collected, concentrated, and dried in-vacuo. This crude material was directly purified by preparative LC/MS (25-85% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording tert-butyl (R)-1-(biphenyl-4-yl)-4-((R)-3-(4-chloro-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate (48C) as a clear oil. ESI-MS: m/z 645.3 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:4].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+].[N-]=C=O>CC#N.C(OCC)(=O)C>[N:22]1([CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[CH:21]=[N:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[CH:7]=2)=[O:4])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCNC1
Reactant: O=C(CCl)Nc1cccc(-c2cnc3ccccc3n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [N-]=C=O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(CN1CCCC1)Nc1cccc(-c2cnc3ccccc3n2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
A solution of 2-chloro-N-(3-quinoxalin-2-ylphenyl)acetamide (100 mg, 0.336 mmol), pyrrolidine (34 μL, 0.403 mmol) and K2CO3 (112 mg, 0.806 mmol) in MeCN (5 mL) was stirred at 50° C. for 18 hrs. HPLC analysis still showed starting material and therefore, the reaction mixture was further stirred at 100° C. for 1 h to afford completion. The mixture was cooled to room temperature and ethyl acetate (20 mL) was added, the organic phase was washed with water (20 mL) and then brine (20 mL), and dried over MgSO4, and solvent evaporated. The resulting oily solid was dissolved in DCM (5 mL) and stirred overnight with polystyrene methylisocyanate (“PS-isocyanate” 276 mg, 0.4 mmol, 1.46 mmol/g) to remove any excess pyrrolidine. The polymer was filtered and the organic phase was remove in vacuo, to afford 2-pyrrolidin-1-yl-N-(3-quinoxalin-2-ylphenyl)acetamide (45 mg, 40% yield). LCMS calculated for C20H20N4O (M+H): 333.41. found 333.21. 1H-NMR (DMSO-d6, 400 Mhz) δH: 9.95 (s, 1H), 9.51 (s, 1H), 8.55 (s, 1H), 8.20-8.14 (m, 2H), 8.08-8.02 (m, 1H), 7.95-7.82 (m, 3H), 7.58-7.50 (m, 1H), 3.40 (s, 2H), 2.65-2.55 (m, 4H), 1.85-1.75 (m, 4H).