Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[CH:11][N:10]([CH3:13])[N:9]=2)=[CH:4][N:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH:25]=[C:24](B(O)O)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C(Cl)Cl.O>[CH3:13][N:10]1[CH:11]=[N:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:24]3[CH2:25][CH2:26][N:21]([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:22][CH:23]=3)=[N:3][CH:4]=2)=[N:9]1
Reactant: CC(C)(C)OC(=O)N1CC=C(B(O)O)CC1
Reactant: Cn1cnc(-c2ccc(Cl)nc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: Cn1cnc(-c2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)nc2)n1

Procedure:
A mixture of 2-chloro-5-(1-methyl-1H-1,2,4-triazol-3-yl)pyridine (3BX) (400 mg, 2.06 mmol); N-Tert-Butoxycarbonyl-1,2,3,6-tetrahydropyridine-4-boronic acid, pinacol ester (1.4 g, 4.53 mmol); Cesium carbonate (2.3 g, 7.07 mmol) and PdCl2dppf (100 mg) in dioxane/H2O (v/v 10:1, 20 ml) was stirred at 100° C. for 2 hours. The reaction was cooled, diluted with CH2Cl2 (300 ml) and H2O (100 ml), organic layer separated, dried over Na2SO4, filtered and solvent evaporated yielding a residue which chromatographed on silica gel eluting with EtOAc yielding title product 4BX as a solid (400 mg, 57%) MS (MH, 342).
Reaction SMILES: P(Cl)(Cl)Cl.[ClH:5].[CH3:6][O:7][C:8](=[O:23])[C:9](Cl)([C:20]#[N:21])[CH2:10][CH:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:12]=O>CN(C=O)C>[Cl:5][C:20]1[C:9]([C:8]([O:7][CH3:6])=[O:23])=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][N:21]=1
Reactant: COC(=O)C(Cl)(C#N)CC(C=O)c1ccccc1
Reactant: Cl
Solvent: ClP(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2ccccc2)cnc1Cl
Temperature: 90 °C

Procedure:
5 g of PCl3 were added to 25 mL of DMF at room temperature. The resulting yellow solution was saturated with anhydrous HCl while keeping the temperature below 90° C. 5 g (18 mmol) of methyl-2-chloro-2-cyano-4-phenyl-5-oxopentanoate in 5 mL DMF were added at 80° C. and the resulting solution heated at 90° C. for 90 min. The reaction mixture was cooled to room temperature, quenched with water, extracted with toluene, dried and distilled to give methyl 2-chloro-5-phenyl-3-pyridine carboxylate.
Reaction SMILES: [Br:1][CH:2]([C:7]([CH:9]1[CH2:11][CH2:10]1)=O)[C:3]([O:5][CH3:6])=[O:4].[NH2:12][C:13]([NH2:15])=[S:14]>C(O)C>[BrH:1].[NH2:15][C:13]1[S:14][C:2]([C:3]([O:5][CH3:6])=[O:4])=[C:7]([CH:9]2[CH2:11][CH2:10]2)[N:12]=1
Reactant: COC(=O)C(Br)C(=O)C1CC1
Reactant: NC(N)=S
Solvent: CCO
Product: Br
Product: COC(=O)c1sc(N)nc1C1CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
Methyl 2-bromo-3-cyclopropyl-3-oxopropanoate (3.3 g) and thiourea (900 mg) were dissolved in ethanol (20 ml) followed by stirring at 80° C. overnight. After cooling to room temperature, the solvent was evaporated under reduced pressure, and the residue was washed with isopropanol to obtain, as a grayish white solid, methyl 2-amino-4-cyclopropyl-1,3-thiazole-5-carboxylate monohydrobromide (2.82 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C:9](=[O:11])[CH2:8][C@H:7]1[C:12](=[O:17])[NH:13][CH2:14][C:15]#[N:16])=[O:5])[CH3:2].CN(C=O)C.[BH4-].[Na+]>C1COCC1>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([OH:11])[CH2:8][C@H:7]1[C:12](=[O:17])[NH:13][CH2:14][C:15]#[N:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(=O)C[C@H]1C(=O)NCC#N
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1C[C@H](O)C[C@H]1C(=O)NCC#N
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of (1R,2R)-2-(cyanomethyl-carbamoyl)-4-oxo-cyclopentanecarboxylic acid ethyl ester (2.7 mmol) in THF (12 ml) was added DMF (1 ml), the solution was cooled to 0° C., sodium borohydride (3.3 mmol) was added and stirring was continued for 2 h. The mixture was partitioned between 1N aqueous HCl and ethyl acetate, the organic layer was dried, evaporated and the residue chromatographed on silica using dichloromethane/MeOH (97:3) to give in the first fraction (1R,2R,4R)-2-(cyanomethyl-carbamoyl)-4-hydroxy-cyclopentanecarboxylic acid ethyl ester as a white solid. MS: 241.4 (M+H)+. The second fraction contained the desired isomer,
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[F:20][C:21]([F:37])([F:36])[CH2:22][NH:23][CH:24]1[CH2:30][CH2:29][C:28]2[CH:31]=[C:32]([NH2:35])[CH:33]=[CH:34][C:27]=2[CH2:26][CH2:25]1.CC1(C)[C@]2(CS(O)(=O)=O)C(C[C@H]1CC2)=O.C(=O)(O)[O-].[Na+]>CC(O)C.O>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:35][C:32]2[CH:33]=[CH:34][C:27]3[CH2:26][CH2:25][CH:24]([NH:23][CH2:22][C:21]([F:20])([F:36])[F:37])[CH2:30][CH2:29][C:28]=3[CH:31]=2)=[N:3][CH:4]=1
Reactant: Nc1ccc2c(c1)CCC(NCC(F)(F)F)CC2
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCC(NCC(F)(F)F)CC3)ncc1Cl
Temperature: 120 °C
Yield: 7.4 %

Procedure:
2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (86.3 mg, 0.290 mmol) and N*7*-(2,2,2-trifluoro-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine (75 mg, 0.290 mmol) were combined with DL-10-camphorsulfonic acid (101 mg, 0.436 mmol) in 2 ml IPA and heated in a microwave vial for 40 minutes at 120° C. for 40 minutes. The resulting reaction was poured into 25 ml saturated sodium bicarbonate solution and 50 ml water and extracted with 4×25 ml portions of methylene chloride. The combined organic was dried over magnesium sulfate, filtered and evaporated. The crude product was purified via reverse phase preparative chromatography (Luna C18, 5 μm, 100 mm×21.2 mm column) using a gradient of 0-35% MeCN in water (both containing 0.1% TFA). 2-{5-Chloro-2-[7-(2,2,2-trifluoro-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamide (11.18 mg, 7.4% yield) was isolated as an off white solid. 1H-NMR (CDCl3) δ 11.07 (s, 1H), 8.66 (d, J=8.44 Hz, 1H), 7.45 (m, 2H), 7.35 (s, 1H), 7.04 (m, 2H), 6.91 (s, 1H), 6.18 (s, 1H), 3.24 (q, J=19.4, 9.8 Hz, 2H), 3.03 (d, J=4.8 Hz, 3H), 2.87 (m, 3H), 2.66 (m, 2H), 2.06 (m, 2H), 1.32 (m, 5H). LC/MS (ESI+)=519 (M+H). MP=202-203° C.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][Br:7].[P:8](OCC)([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])=[O:9]>>[Br:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][P:8](=[O:9])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]
Reactant: CCOP(=O)(OCC)OCC
Reactant: BrCCOCCBr
Product: CCOP(=O)(CCOCCBr)OCC
Temperature: 160 °C

Procedure:
1-bromo-2-(2-bromoethoxy) ethane (1.0 eq) was mixed with triethyl phosphate (1 eq) then heated to 160° C. for 20 minutes by microwave. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 70-100% EtOAc/Hex to give the product as a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O.CC(O)=O.[Rh]>[C:21]([N:1]1[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH:3]([C:10]([OH:12])=[O:11])[CH2:2]1)([O:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:22]
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Rh]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)C2CCCCC12
Reaction time: 30 h
Yield: 34.2 %

Procedure:
A solution of 25 g (155 mmol) of indole-3-carboxylic acid in 1500 mL H2O and 150 mL HOAc was charged with 25 g of 5% Rh/Al2O3 and the mixture hydrogenated at 60 psi for 30 hr at 60° C. The mixture was filtered through Celite® and evaporated in vacuo to a dark oil which was treated with benzylchloroformate (26.35 g; 155 mmol) under basic conditions substantially according to the procedures of Example 15, A. The crude product crystallized out of hot CH2Cl2 /hexanes to yield 16.06 g (53 mmol; 49%) of N-Cbz-3-perhydroindolylcarboxylic acid as a white solid.
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.[C:11]1([CH2:17][CH2:18]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.Cl.[CH3:28][N:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1>C(O)C>[CH3:28][N:29]1[CH2:34][CH2:33][C:32]2[N:8]([CH2:18][CH2:17][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:5]3[CH:4]=[CH:3][C:2]([CH3:10])=[CH:7][C:6]=3[C:31]=2[CH2:30]1
Reactant: BrCCc1ccccc1
Reactant: Cc1ccc(NN)cc1
Reactant: CN1CCC(=O)CC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)c1c(n2CCc2ccccc2)CCN(C)C1
Temperature: 80 °C
Reaction time: 16 h
Yield: 3.9 %

Procedure:
Preparation of the title compound was carried out according to General Method 8. p-Tolylhydrazine hydrochloride (2 g, 12.6 mmol), 2-phenyl ethyl bromide (1.7 ml, 12.6 mmol) and triethyl amine (1.7 mL, 12.6 mmol) in ethanol (6 ml) were stirred at 25° C. for 1 h after which the contents were heated at 80° C. for 2 h. The contents were cooled to 25° C., N-methyl-4-piperidone hydrochloride (2.87 g, 18.9 mmol) was added and heating was continued at 80° C. for 16 h. The contents were concentrated in vacuo, basified by adding saturated aqueous NaHCO3, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (230-400 mesh) using ethyl acetate-hexane gradient to obtain 150 mg of 2,3,4,5-tetrahydro-2,8-dimethyl-5-phenethyl-1H-pyrido[4,3-b]indole. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[N+:19]([O-])=O)=[CH:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].CO>[Pd].O1CCCC1>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[NH2:19])[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C2=CCC(C(C)(C)C)CC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C2CCC(C(C)(C)C)CC2)c(N)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 1-(4-t-butylcyclohex-1-enyl)-4-methoxy-2-nitrobenzene (2.89 g, 10.0 mmol) prepared in Example (12a), 10% palladium on carbon (1.0 g, wet), methanol (15 mL) and tetrahydrofuran (15 mL) was stirred for 12 hours under hydrogen atmosphere at atmospheric pressure and room temperature.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=[O:12])[CH2:8][CH2:7]2.[BH4-].[Na+].O>CO>[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]2
Reactant: Nc1cccc2c1CC(=O)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1cccc2c1CC(O)CC2
Reaction time: 1 h
Yield: 71.3 %

Procedure:
Next, to a solution of 8-amino-3,4-dihydronaphthalen-2(1H)-one (0.050 g, 0.318 mmol) in methanol (10 ml) was added sodium borohydride (0.030 g, 0.175 mmol) at 0° C., and the mixture was stirred for 1 hour. The mixture was poured into water, and the product was extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 8-amino-1,2,3,4-tetrahydro-naphthalen-2-ol (0.037 g, 71% yield).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.C(O[CH:15]=[C:16]([C:22]#[N:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:23][C:22]1[N:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[N:11]=[CH:15][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: COc1ccc(NN)cc1
Reactant: CCOC=C(C#N)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ccc(OC)cc2)c1N
Temperature: 0 °C
Yield: 28.2 %

Procedure:
Twenty grams of (4-methoxyphenyl)hydrazine hydrochloride, 18.6 g of ethyl (ethoxymethylene)cyanoacetate and 15.2 g of potassium carbonate were combined with 200 ml of ethanol and refluxed for 20 hours. The mixture was cooled and poured into ice water. The precipitated solid was collected by filtration, dried and recrystallized from ethanol to afford 8.1 g of 5-amino-1-(4-methoxyphenyl)-1H-pyrazole-4-carboxylic acid, ethyl ester. Yield 28%. mp=209°-211° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH3:9])[CH:3]=1.[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.ClCCl>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][Br:10])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Br)ccc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Clc1ccc(Br)cc1CBr
Yield: 69.7 %

Procedure:
A mixture of 4-bromo-1-chloro-2-methylbenzene (5.0 g, 24.0 mmol), N-bromosuccinimide (4.4 g, 25.0 mmol), and benzoyl peroxide (700 mg, 2.9 mmol) in anhydrous carbon tetrachloride (85 mL) was stirred at reflux for 4 hours. Dichloromethane (50 mL) was added. The mixture was extracted with 1 N NaOH (1×150 mL) and brine (1×150 mL). The organic extract was recovered, dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude product was purified by flash chromatography (0-5% EtOAc/hexanes), affording 4-bromo-2-(bromomethyl)-1-chlorobenzene (4.76 g, 70% yield). The product was used without further purification.
Reaction SMILES: C(OC([N:8]1[C:12]([CH:13]2[CH2:16][CH:15]([O:17][C:18](=[O:24])[NH:19][CH2:20][CH:21]3[CH2:23][CH2:22]3)[CH2:14]2)=[CH:11][C:10]([NH:25][C:26](=[O:36])[C:27]([CH3:35])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH3:28])=[N:9]1)=O)(C)(C)C.C(OC(N1C(NC(=O)C(C)(C2C=CC=CN=2)C)=CC(C2CC(OC(=O)NCC3CC3)C2)=N1)=O)(C)(C)C.C(Cl)Cl>C(O)(C(F)(F)F)=O.CCOC(C)=O>[CH3:35][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)([CH3:28])[C:26]([NH:25][C:10]1[CH:11]=[C:12]([CH:13]2[CH2:14][CH:15]([O:17][C:18](=[O:24])[NH:19][CH2:20][CH:21]3[CH2:23][CH2:22]3)[CH2:16]2)[NH:8][N:9]=1)=[O:36]
Reactant: CC(C)(C)OC(=O)n1nc(NC(=O)C(C)(C)c2ccccn2)cc1C1CC(OC(=O)NCC2CC2)C1
Agent: CC(C)(C)OC(=O)n1nc(C2CC(OC(=O)NCC3CC3)C2)cc1NC(=O)C(C)(C)c1ccccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C(=O)Nc1cc(C2CC(OC(=O)NCC3CC3)C2)[nH]n1)c1ccccn1
Reaction time: 4 h

Procedure:
A mixture of 5-(3-cyclopropylmethylcarbamoyloxy-cyclobutyl)-3-(2-methyl-2-pyridin-2-yl-propionylamino)-pyrazole-1-carboxylic acid tert-butyl ester and 3-(3-cyclopropylmethylcarbamoyloxy-cyclobutyl)-5-(2-methyl-2-pyridin-2-yl-propionylamino)-pyrazole-1-carboxylic acid tert-butyl ester (120 mg, prepared by procedures analogous to those described in Example 221, Steps A to E, using appropriate starting materials) was dissolved in TFA (0.19 mL) and CH2Cl2 (1.25 mL) at room temperature. After 4 h, the solution was diluted with EtOAc and the solution was washed sequentially with saturated aqueous NaHCO3 solution (2×), water, and saturated aqueous NaCl solution. The organic layer was dried over Na2SO4 and concentrated. Purification of the residue by silica gel chromatography afforded the title compound as a solid. MS (M+H)+=398.3.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.CS(O)(=O)=O.[NH2:30][CH2:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[C:37](=[O:41])[N:36]([CH:42]1[CH2:47][CH2:46][C:45](=[O:48])[NH:44][C:43]1=[O:49])[C:35]2=[O:50].O>CN(C)C=O.CO>[O:49]=[C:43]1[CH:42]([N:36]2[C:35](=[O:50])[C:34]3[C:38](=[CH:39][CH:40]=[C:32]([CH2:31][NH:30][C:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:9][N:8]=4)=[O:12])[CH:33]=3)[C:37]2=[O:41])[CH2:47][CH2:46][C:45](=[O:48])[NH:44]1
Reactant: CCOc1ccc(C(=O)O)nc1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CCOc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2CCC(=O)NC2=O)C3=O)nc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
A stirred mixture of 5-ethoxy-pyridine-2-carboxylic acid (0.50 g, 3.00 mmol) and CDI (0.54 g, 3.30 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 1 h, 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione methane sulfonate (1.15 g, 3.00 mmol) was added and the mixture was heated at 40° C. for 1.5 h. The mixture was cooled to rt and water (40 mL) was added. After 2 h, the solids were isolated by filtration. The product was dissolved in MeOH (200 mL) and treated with decolorizing carbon. The carbon was removed by filtration and the filtrate was concentrated until precipitation was observed. The product was isolated by filtration, washed with MeOH (5 mL) and dried in vacuo to give 5-ethoxy-pyridine-2-carboxylic acid[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.89 g, 68% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 4.24 min (99.33%); mp: 185-187° C.; 1H 1H NMR (DMSO-d6) δ 1.37 (t, J=7.0 Hz, 3H, CH3), 1.95-2.16 (m, 1H, CHH), 2.40-2.70 (m, 2H, CHH, CHH), 2.78-3.01 (m, 1H, CHH), 4.19 (q, J=7.0 Hz, 2H, CH2), 4.63 (d, J=6.2 Hz, 2H, CH2), 5.14 (dd, J=5.4, 12.9 Hz, 1H, CH), 7.53 (dd, J=2.9, 8.8 Hz, 1H, Ar), 7.74-7.93 (m, 3H, Ar), 8.00 (d, J=8.7 Hz, 1H, Ar), 8.32 (d, J=2.5 Hz, 1H, Ar), 9.42 (t, J=6.4 Hz, 1H, NH), 11.11 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.40, 21.99, 30.93, 42.30, 48.99, 64.07, 121.27, 122.07, 123.39, 123.50, 129.74, 131.54, 133.54, 136.79, 142.16, 147.74, 156.99, 164.09, 167.00, 167.15, 169.80, 172.73; LCMS: MH=437; Anal Calcd for C22H20N4O6: C, 60.55; H, 4.62; N, 12.84. Found: C, 60.19; H, 4.53; N, 12.71.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[C:7]=1[NH2:15].[OH-].[Na+]>C(OCC)(=O)C.C(O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[C:7]=1[NH2:15]
Reactant: COCCOc1cccc([N+](=O)[O-])c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COCCOc1cccc(N)c1N

Procedure:
To a solution of 1 g 2-(2-Methoxy-ethoxy)-6-nitro-phenylamine in 10 mL ethyl acetate and 3 mL ethanol, 4.4 g SnCl2 dihydrate were added and the reaction mixture was heated to reflux for 6 h. Then, after cooling 50 mL 2 M NaOH were added and the inorganic precipitate was filtered and washed extensivley with ethyl acetate. The filtrate was extracted with exthyl acetate (3×100 ml), the combined organic layers were dried over MgSO4, and the solvents were removed under reduced pressure. The remaining product was pure enough for the next reaction step.
Reaction SMILES: [OH:1][C@H:2]([C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH:3]=[CH2:4].C12BC(CCC1)CCC2.[OH-:30].[Na+].OO>O1CCCC1.O>[OH:30][CH2:4][CH2:3][C@H:2]([OH:1])[C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: [OH-]
Reactant: C=C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)CCO
Temperature: 50 °C
Yield: 100.4 %

Procedure:
The resultant compound from Example 121 (327.6 mg, 1.16 mmol) in tetrahydrofuran (THF, 2 ml) at 0° C. was treated with 9-borabicyclo(3.3.1)nonane (4.6 ml, 2.2 mmol in THF). After 3 h at room temperature water (0.1 ml) then NaOH (280 mg, 7.0 mmol) in water (1 ml) then 30% H2O2 (0.70 ml, 6.9 mmol) were added and the mixture was heated at 50° C. for 90 min. The mixture was concentrated, dissolved in ethyl acetate, washed with brine, dried over Na2SO4, evaporated and chromatographed on silica gel with 2% methanol in chloroform to give 351.1 mg (100%) of the desired compound as an oil. DCI-MS: (M+H)=302.
Reaction SMILES: [CH3:1][P:2](Cl)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[CH3:11][O:12][C:13](=[O:23])[C@@H:14]([CH3:22])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:11][O:12][C:13](=[O:23])[C@@H:14]([CH3:22])[N:15]([P@@:2]([CH3:1])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CP(=O)(Cl)c1ccccc1
Reactant: CCCCCCN[C@H](C)C(=O)OC
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCN([C@H](C)C(=O)OC)[P@](C)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Methylphenyl-phosphinic chloride (1.05 g, 6 mmol) is dissolved in dichloromethane (50 mL) and cooled to 0° C. To this is added a solution of N-hexyl-D-alanine methyl ester (1 g, 5.34 mmol) and triethylamine (2.1 mL, 15 mmol) in dichloromethane (10 mL). A catalytic amount of 4-dimethylaminopyridine is added and reaction is stirred for 16 hours, washed with water and brine, dried over sodium sulfate, and concentrated. The crude product is purified by silica gel flash chromatography (100% ethyl acetate) to give N-((R)-methylphenylphosphinyl)-N-hexyl-D-alanine methyl ester as an oil.
Reaction SMILES: [CH2:1]([C:8]1([C:21](=[O:35])[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30](=[O:34])[N:31]([CH3:33])[CH3:32])[CH:24]=2)[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1>CO>[CH3:33][N:31]([CH3:32])[C:30](=[O:34])[O:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([NH:22][C:21]([C:8]2([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[O:35])[CH:24]=1
Reactant: CN(C)C(=O)Oc1cccc(NC(=O)C2(Cc3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CN(C)C(=O)Oc1cccc(NC(=O)C2(Cc3ccccc3)CCNCC2)c1
Temperature: 50 °C

Procedure:
To a solution of tert-butyl 4-benzyl-4-(3-(dimethylcarbamoyloxy)-phenylcarbamoyl)piperidine-1-carboxylate from step A (0.162 g, 0.336 mmol) in MeOH (5 mL) was added 4 M HCl in dioxane (0.250 mL, 1.00 mmol). The reaction was heated at 50° C. for 1 hour, and then concentrated under vacuum, re-dissolved in MeOH and re-concentrated twice to give the title compound as the hydrochloride salt. MS (ES+) [M+H]+=382.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Br:17][CH2:18][C:19](Br)=[O:20]>C(OCC)(=O)C>[CH3:1][N:2]([C:19](=[O:20])[CH2:18][Br:17])[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Br)CBr
Reactant: CNc1ccc(Cl)cc1Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN(C(=O)CBr)c1ccc(Cl)cc1Cc1ccccc1
Reaction time: 1 h

Procedure:
The N-methyl 2-benzyl-4-chloroaniline (10.8 g) in solution in ethyl acetate is treated at 5° C. with 4.9 ml of bromoacetyl bromide. After 1 hour at room temperature, decantation and washing with water, the solution is concentrated. Upon crystallization, N-methyl 2'-benzyl-4'-chloro-bromoacetanilide is obtained (12.21 g). MP = 78° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:8]=[C:7]2[Cl:16].[CH2:17](N(CC)CC)[CH3:18]>C(O)C>[Cl:16][C:7]1[C:6]2[C:11](=[C:2]([CH:17]=[CH2:18])[CH:3]=[CH:4][CH:5]=2)[N:10]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:8]=1
Reactant: CCN(CC)CC
Reactant: FC(F)(F)c1cc(Cl)c2cccc(Br)c2n1
Solvent: CCO
Product: C=Cc1cccc2c(Cl)cc(C(F)(F)F)nc12
Yield: 72.7 %

Procedure:
A suspension of 2.00 g (6.25 mmol) 8-bromo-4-chloro-2-trifluoromethylquinoline (commercially available from Maybridge, Cornwall, UK), 258 mg (0.31 mmol) PdCl2dppf CH2Cl2, 1.29 g (9.37 mmol) potassium vinyl tetrafluoroborate and 0.88 ml (6.28 mmol) triethylamine in 40 ml ethanol was heated at reflux for 3 h. The resulting yellow suspension was filtered and the filtrate evaporated to dryness. The residue was suspended in ethyl acetate, filtered and the filtrate extracted with water. The organic layer was evaporated to dryness and the isolated crude product purified by silica gel chromatography (hexane) to yield 1.17 g (72%) of the title compound as white crystals. MS: 257.1 (M+). 1H-NMR (300 MHz, CDCl3): 5.58 (dd, J=11.1, 1.1 Hz, 1H); 6.07 (dd, J=17.8, 1.1 Hz, 1H); 7.75 (t, J=7.7 Hz, 1H); 7.81 (s, 1H); 7.99 (dd, J=17.8, 1.1 Hz, 1H); 8.09 (d, J=7.2 Hz, 1H); 8.23 (d, J=8.4 Hz, 1H).