Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][CH2:12][O-].[Na+].O1CCOCC1.S(OCC)(OCC)(=O)=O>O>[O:1]([CH2:8][CH2:9][O:10][CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCOc1ccccc1
Reactant: CC[O-]
Agent: CCOS(=O)(=O)OCC
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOCCOc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
143.0 g (1.04 mol) of 2-phenoxyethanol, 81.0 g (1.19 mol) of sodium ethylate and 291 g of 1,4-dioxane are placed in a 1-liter four-necked flask equipped with a stirrer, a thermometer, a distillating column and a nitrogen-inlet tube. The solution is heated to 90° to 105° C., and then 200 g of the solvent is removed in a period of 2 hours. The distillating column is then replaced by a dropping funnel, and 183.5 g (1.19 mol) of diethyl sulfate is added thereto dropwise at 45° C. over a period of 30 minutes. After stirring the reaction mixture at 60° C. for 1 hour, the reaction product is placed in water and extracted with ether. The solvent is removed using an evaporator, and further distilled under reduced pressure to yield 160 g of ethyl 2-phenoxyethyl ether.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([CH:17]=[N:18]O)[N:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([C:17]#[N:18])[N:3]=1
Reactant: Nc1nc(N)c(-c2ccc(Cl)cc2Cl)c(C=NO)n1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: N#Cc1nc(N)nc(N)c1-c1ccc(Cl)cc1Cl

Procedure:
This compound was prepared from the compound of Example 48 by reaction with trifluoroacetic anhydride in pyridine, mp. 249° C.
Reaction SMILES: [H-].[Na+].CO.[C:5]([CH2:7][C:8]([NH2:10])=[O:9])#[N:6].[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19](=O)[C:20]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)=[CH:21]N(C)C>CN(C=O)C>[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19]1[NH:10][C:8](=[O:9])[C:7]([C:5]#[N:6])=[CH:21][C:20]=1[C:25]1[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=1
Reactant: N#CCC(N)=O
Reactant: Cc1ccc(C(=CN(C)C)C(=O)c2ccc(Cl)cc2Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc(-c2cc(C#N)c(=O)[nH]c2-c2ccc(Cl)cc2Cl)cc1
Temperature: 95 °C
Reaction time: 3 h

Procedure:
To a dried round bottom flask was added NaH (3.73 g in 60% disp.; 93.3 mmol), DMF (100 mL), and methanol (3.78 mL; 93.3 mmol) under a nitrogen atmosphere. To this suspension was added a solution of 2-cyanoacetamide (3.92 g; 46.6 mmol) in DMF (30 mL) via syringe. Then a solution of the crude product of Step B (42.4 mmol) in DMF (30 mL) was added via syringe. The resulting reaction mixture was heated to 95° C. and stirred for 3 hours. The reaction was quenched with saturated aq. NaHSO4 solution and extracted with methylene chloride (3×). The combined extracts were dried (Na2SO4), filtered, and concentrated in vacuo. Purification was done by trituration in ethanol. The precipitate was collected and washed with cold ethanol to afford the desired product: m/e=355 (M+1) Rt=3.3 min on LCMS.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][C@@H:9]1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:19][C:20]1([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[CH2:22][CH2:21]1.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:30][O:29][C:27]([C:26]1[CH:31]=[CH:32][C:23]([C:20]2([NH:19][C:15]([C@H:9]3[CH2:10][C:11]([CH3:13])([CH3:14])[CH2:12][N:8]3[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:17])[CH2:21][CH2:22]2)=[CH:24][CH:25]=1)=[O:28]
Reactant: CC1(C)C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CC(C)(C)CN3C(=O)OC(C)(C)C)CC2)cc1
Yield: 65.4 %

Procedure:
The title compound (D75) (94 mg) was prepared according to the general procedure for amides preparation (Method C) starting from (R)-1-(tert-butoxycarbonyl)-4,4-dimethylpyrrolidine-2-carboxylic acid (D41) (84 mg) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (79 mg). HCTU: 1.05 eq; Reaction time: 2 hrs.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>C(Cl)Cl.O>[C:9]([O:8][C:7]([NH:6][C@@H:3]1[CH2:4][CH2:5][N:1]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:2]1)=[O:13])([CH3:10])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Yield: 84.9 %

Procedure:
A solution of tert-Butyl (3S)-pyrrolidin-3-ylcarbamate (10.0 g, 53.7 mmol) in DCM (40 ml) was treated with TEA (14.9ml, 107 mmol) and cooled to 0° C. Benzyl chloroformate (7.6 ml, 53.7 mmol) was added dropwise and the resulting suspension was allowed to warm gradually to room temperature over a period of 18 hours. The reaction mixture was diluted with water (100 ml) and the organic phase separated. The aqueous phase was extracted with further DCM (2×50 ml) and the combined organic extracts dried (sodium sulphate) and concentrated in vacuo to give a pale yellow solid (14.6 g, 85%)
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[C:10]([O:14][C:15]([N:17]1[C@H:22]([CH2:23][NH2:24])[C@@H:21]2[CH2:25][C@H:18]1[CH2:19][CH2:20]2)=[O:16])([CH3:13])([CH3:12])[CH3:11].CCN(C(C)C)C(C)C>C1COCC1>[C:10]([O:14][C:15]([N:17]1[C@H:22]([CH2:23][NH:24][C:3](=[O:5])[C:2]([F:1])([F:8])[F:9])[C@@H:21]2[CH2:25][C@H:18]1[CH2:19][CH2:20]2)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1CN
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1CNC(=O)C(F)(F)F

Procedure:
Ethyl trifluoroacetate (12.2 mmol, 1.30 eq) is added to a solution of (1R,3S,4S)-3-aminomethyl-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (9.42 mmol, 1.00 eq) and DIPEA (14.1 mmol, 1.50 eq) in THF (25 mL). After 50 min the mixture is concentrated in vacuo, diluted with TBME (100 mL) and washed twice with aq. citric acid (5%) and water respectively. The organic layer is dried over MgSO4 and concentrated in vacuo to give a crude product which is used without further purification. LC-MS (basic): tR=0.95 min; [M+H]+=323.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH2:6].[N+](=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N-]>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]2[CH2:6][CH:12]2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1cccc(F)c1
Product: CCOC(=O)C1CC1c1cccc(F)c1
Yield: 54.9 %

Procedure:
3-Fluorostyrene (9.7 mL, 82 mmol) and ethyl diazoacetate (8.6 mL, 82 mmol) were reacted by the method reported in Org. Syn. Coll. Vol. VI, 1988, 913. The product was purified on silica. 9.4 g of ethyl 2-(3-fluorophenyl)cyclopropane carboxylate (45 mmol, 55%) was obtained. MS (GC/MS, EI) 208 (M+). (b) The trans ester was selectively hydrolyzed from the cis/trans mixture by the method reported in Org. Syn. Coll. Vol. VI, 1988, 913. Recrystallize from hexane to yield 2.5 g (13.9 mmol, 89% of the trans) of trans-2-(3-fluorophenyl)cyclopropane carboxylic acid. (c) The trans-2-(3-fluorophenyl)cyclopropane carboxylic acid (400 mg, 2.2 mmol) and (R)-3-methoxyphenyl ethylamine (280 mg, 1.9 mmol) were converted to the diastereomeric amides by the method reported in Aust. J. Chem. 1984, 37, 1709. 446 mg (1.4 mmol, 75%) of trans-2-(3-fluorophenyl)-N-(1(R))-(3-methoxyphenyl)ethyl)cyclopropane carboxamide was obtained. MS (GC/MS, EI) 313 (M+). (d) The mixture of diastereomeric amides (550 mg, 1.8 mmol) were reduced to the amines with BH3.THF (7 mL, 7.0 mmol) in 10 mL THF. Upon complete addition, the solution was heated to reflux, overnight. The solution was cooled to 0° C. and 7 mL of 6 N HCl was carefully added. This was stirred open to air for two hours, THF was removed in vacuo. The aqueous residue was basified to pH 9 with Na2CO3 solution and extracted with 3×20 mL CH2Cl2. The combined extracts were washed with 20 mL water and 20 mL of 1:1 water/brine. The organics were dried (Na2SO4), filtered, and solvent was removed. 520 mg of N-(trans-2-(3-fluorophenyl)cyclopropanylmethyl)-1-(R)-(3-methoxyphenyl)ethylamine (1.8 mmol, 99%) was obtained as an oil. MS (CI) m/z 300 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:7][C:8]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:9])[C:4]([OH:6])=O.[CH:16]1[C:26]2[CH:25]=[CH:24][C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[C:21](=[C:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[C:20]=2[CH:19]=[CH:18][CH:17]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl>[CH:16]1[C:26]2[CH:25]=[CH:24][C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[C:21](=[C:31]3[CH2:32][CH2:33][N:34]([C:4](=[O:6])[CH:3]([NH:7][C:8]([N:10]4[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]4)=[O:9])[CH2:2][OH:1])[CH2:35][CH2:36]3)[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)C(CO)NC(=O)N1CCCCC1
Reactant: C1=Cc2ccccc2C(=C2CCNCC2)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC(CO)C(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
64.0 mg (0.296 mmol) of 3-hydroxy-2-[(1-piperidinylcarbonyl)amino]propionic acid, 80.9 mg (0.296 mmol) of 4-(5H-dibenzo[a,d][7]annulen-5-ylidene)piperidine and 85.1 mg (0.444 mmol) of 1 -ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride were dissolved in 10 ml of dichloromethane. 0.091 ml (0.651 mmol) of triethylamine was added to the obtained solution, and they were stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue. After washing with saturated aqueous sodium chloride solution, the reaction product was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant product was purified by the silica gel chromatography (dichloromethane: methanol=9:1) to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([S:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:8][CH:7]=1)=[O:4].[H-].[K+].[CH3:23]I>C1COCC1.CCOCC>[CH3:20][N:2]([CH3:1])[C:3]([S:5][C:6]1[CH:7]=[CH:8][C:9]([C:12](=[O:19])[CH:13]([CH3:23])[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:11]=1)=[O:4]
Reactant: COC(=O)CCC(=O)c1ccc(SC(=O)N(C)C)cc1
Reactant: CI
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)CC(C)C(=O)c1ccc(SC(=O)N(C)C)cc1
Temperature: -45 °C
Reaction time: 0.5 h

Procedure:
The compound from Step D, (10.0 g, 33.9 mmoles) was dissolved in THF (100 ml) and added dropwise to a stirred mixture of potassium hydride (1.6 g, 40.7 mmoles) in THF (10 ml) at -45° C. The reaction mixture was warmed to 0° to initiate the reaction, then cooled to -45° C. After 30 minutes, the reaction mixture was warmed to 0° C., and stirred for 10 minutes A solution of methyl iodide (3.17 ml, 50.9 mmoles) in THF (10 ml) was added slowly to the cold solution. The mixture was stirred at 0° for one hour. The reaction mixture was diluted with ether, washed with water, brine, dried and evaporated to yield an oil which was purified by HPLC to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:21])[C:6]2[CH2:7][CH:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH2:9][CH2:10][C:11]=2[CH:12]=1.[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33]([O:21][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[C:11]3[C:6]=2[CH2:7][CH:8]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[CH2:9][CH2:10]3)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: COc1ccc(C2CCc3cc(OC)cc(O)c3C2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C2CCc3cc(OC)cc(Oc4ccc(OCc5ccccc5)cc4)c3C2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 85.7 %

Procedure:
The title compound was synthesized by referring to Tetrahedron Lett., 1998, 39 (19), 2937-2940. To a solution of 3-methoxy-7-(4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-1-ol (853 mg) and 4-benzyloxyphenylboronic acid (1.4 g) in dichloromethane (30 ml) were sequentially added copper(II) acetate (545 mg), molecular sieves 4A and triethylamine (1.5 g), and the solution was stirred for 8 hours and 40 minutes at room temperature. The insoluble material was filtered through celite pad, the filtrate was adsorbed onto silica gel and purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (1.2 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:18]I.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:18])[C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1ccc(N)cn1
Reaction time: 0.67 h

Procedure:
To a solution of 12-2 (6.0 g, 22.0 mmol) in 50 mL DMF at 0° C. was added NaH gradually. After the mixture was stirred for 40 min, CH3I (3.4 g, 24.0 mmol) was added in one portion. The reaction mixture was stirred for 5 hr, treated with 300 mL water and extracted three times with ethyl ether. The combined organic layers were washed with brine and dried over Na2SO4. After solvent removal, the residue was purified by silica gel flash chromatography (CHCl3/hexanes 6:1) to afford the desired product 12-3 as a solid.
Reaction SMILES: [C:1]12([N:6]3[C:10]4[N:11]=[C:12](Cl)[N:13]=[CH:14][C:9]=4[C:8]([C:16]([C:18]4[CH:19]=[N:20][CH:21]=[C:22]([Br:24])[CH:23]=4)=[O:17])=[CH:7]3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:1]12([N:6]3[C:10]4[N:11]=[C:12]([NH:32][CH2:31][C:30]5[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=5)[N:13]=[CH:14][C:9]=4[C:8]([C:16]([C:18]4[CH:19]=[N:20][CH:21]=[C:22]([Br:24])[CH:23]=4)=[O:17])=[CH:7]3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2
Reactant: COc1ccc(CN)cc1
Reactant: O=C(c1cncc(Br)c1)c1cn(C23CC(C2)C3)c2nc(Cl)ncc12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2ncc3c(C(=O)c4cncc(Br)c4)cn(C45CC(C4)C5)c3n2)cc1
Temperature: 110 °C
Yield: 84 %

Procedure:
To a solution of (7-Bicyclo[1.1.1]pent-1-yl-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(5-bromo-pyridin-3-yl)-methanone (Preparation 284, 1.1 g, 2.72 mmol) and 4-methoxy benzyl amine (1.06 mL, 8.16 mmol) in dioxane (40 mL), DIPEA (1.7 mL, 10.8 mmol) was added and mixture was heated at 110° C. under microwave irradiation for 6 hours. The volatiles were removed in vacuo and the residue was partitioned between water (50 mL) ethyl acetate (150 mL). Organic phase was dried over sodium sulphate, evaporated in vacuo and purified by column chromatography on silica gel (gradient of EA:Hexane 25:75) to afford the title compound as off white solid in 84% yield, 1.15 g.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)[CH3:2].CCN(C(C)C)C(C)C.[CH2:23]([O:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)[O:29][CH2:30][C:31](Cl)=[O:32])[CH3:24]>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:31](=[O:32])[CH2:30][O:29][C:28]2[CH:34]=[CH:35][CH:36]=[C:26]([O:25][CH2:23][CH3:24])[CH:27]=2)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)[CH3:2]
Reactant: CCOc1cccc(OCC(=O)Cl)c1
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cccc(OCC(=O)Nc2ccc(OCC)cc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
A 1 L 3-neck flask fitted with a stir-bar, addition funnel, and an Ar inlet was charged with aniline 46a (9.57 g, 52.6 mmol) and CH2Cl2 (200 mL). The resultant solution was cooled in an ice bath and iPr2NEt (20.4 g, 27.5 mL, 158 mmol) was added followed by acid chloride 47a (14.1 g, 65.7 mmol) in CH2Cl2 (120 mL) over 30 min. The mixture stirred at rt overnight. The red solution was diluted with CH2Cl2 (250 mL) and was washed with saturated aqueous NH4Cl (200 mL), saturated NaHCO3 (200 mL), and brine (200 mL). The organic phase was filtered through phase separation paper and concentrated in vacuo to an orange solid. The solid was triturated with EtOH (75 mL), filtered, pressed with a rubber dam, and rinsed with EtOH (3×20 mL). The solid dried to give 14.3 g of 48a as a yellow solid (80%). 1H NMR (300 MHz, CDCl3): δ 11.36 (s, 1H), 8.78 (d, 1H), 7.72 (d, 1H), 7.30-7.20 (m, 2H), 6.67-6.59 (m, 3H), 4.66 (s, 2H), 4.09 (qt, 2H), 4.07 (qt, 2H), 1.44 (t, 3H), 1.42 (t, 3H) ppm. HPLC analysis (0:10:90 H2O:A1:MeOH) showed a purity of 98% with a retention time of 4.8 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([CH:20]=[O:21])[CH:19]=1)[CH2:5][N:6]([CH:14]1[CH2:16][CH2:15]1)[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].CC1(C)C(C)(C)OB(/[CH:30]=[CH:31]/[CH2:32][O:33][CH3:34])O1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[CH:14]1([N:6]([CH2:5][C:4]2[CH:3]=[C:2](/[CH:30]=[CH:31]/[CH2:32][O:33][CH3:34])[CH:19]=[C:18]([CH:20]=[O:21])[CH:17]=2)[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:16][CH2:15]1
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N(Cc1cc(Br)cc(C=O)c1)C1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC/C=C/c1cc(C=O)cc(CN(C(=O)OC(C)(C)C)C2CC2)c1
Temperature: 90 °C

Procedure:
To a solution of tert-butyl (3-bromo-5-formylbenzyl)cyclopropylcarbamate (1 eq.) from the previous step and 4,4,5,5-tetramethyl-2-[(1E)-3-(methyloxy)-1-propen-1-yl]-1,3,2-dioxaborolane (1 eq.) in DMF (0.2 M) was added trans-bis(triphenylphosphine) palladium(II) bromide (0.05 eq.). The vessel was repeatedly evacuated and back-filled with nitrogen. Finally, 2 M aq. Na2CO3 (3 eq.) was added and the resulting mixture was heated at 90° C. for 6 h. The now black suspension was cooled to RT, diluted with water and extracted with ether. The combined organic extracts were washed further with 10% aq. HCl, 1 N aq. NaOH, water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, Hex→3:7 (v/v) Hex:EtOAc) afforded the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([B:17]([OH:19])[OH:18])=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:20]C1C=C(F)C=CC=1N1C2=NC=CC(I)=C2C=N1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C([O-])(=O)C.[K+]>CS(C)=O>[F:20][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N:8]1[C:12]2=[N:13][CH:14]=[CH:15][C:16]([B:17]([OH:19])[OH:18])=[C:11]2[CH:10]=[N:9]1
Reactant: Fc1ccc(-n2ncc3c(I)ccnc32)c(F)c1
Reactant: OB(O)c1ccnc2c1cnn2-c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [K+]
Solvent: CS(C)=O
Product: OB(O)c1ccnc2c1cnn2-c1ccc(F)cc1F
Temperature: 85 °C

Procedure:
Intermediate 63A was prepared according to the general procedure described in Intermediate 5A, except that the reaction mixture was heated at 85° C. for 75 min, using Intermediate 13A (100 mg, 0.280 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (133.1 mg, 0.524 mmol), potassium acetate (115.0 mg, 1.172 mmol), and DMSO (1.5 mL). The desired product was confirmed to be present by LC/MS (Condition B): 76%; ret. T=2.9 min; (M+H)+ 276.00.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]3[N:17]=[C:16]([N:18]4[CH:22]=[C:21]([CH:23]=O)[C:20]([CH3:25])=[N:19]4)[CH:15]=[CH:14][N:13]=3)[CH:9]=2)[N:4]([CH3:26])[C:3]=1[CH3:27].Cl.[O:29]1[CH2:33][C@@H:32]([OH:34])[CH2:31][NH:30]1.C(N(CC)CC)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]3[N:17]=[C:16]([N:18]4[CH:22]=[C:21]([CH2:23][N:30]5[CH2:31][C@H:32]([OH:34])[CH2:33][O:29]5)[C:20]([CH3:25])=[N:19]4)[CH:15]=[CH:14][N:13]=3)[CH:9]=2)[N:4]([CH3:26])[C:3]=1[CH3:27]
Reactant: Cc1nn(-c2ccnc(Nc3ccc4c(c3)c(Cl)c(C)n4C)n2)cc1C=O
Reactant: O[C@H]1CNOC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nn(-c2ccnc(Nc3ccc4c(c3)c(Cl)c(C)n4C)n2)cc1CN1C[C@H](O)CO1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a slurry of Intermediate 3 (190 mg, 0.5 mmol), (S)-isoxazolidin-4-ol hydrochloride (95 mg, 0.75 mmol) and triethylamine (0.4 mL) in 10 mL of dichloromethane, was added NaBH(OAc)3 (0.32 g, 1.5 mmol) at room temperature. The reaction was stirred for 12 hour at room temperature and then quenched with 1N—NaOH. It was extracted with ethyl acetate and washed twice with brine. The collected organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo. The resulting residue was purified by silica gel chromatography (DCM/MeOH) to afford desired Compound No. 31 as a pale yellow solid (159 mg, 70%); MS (ESI) m/z 454 [M+H]+. 1H NMR (300 MHz, CDCl3) δ 8.43 (s, 1H), 8.34 (d, J=5.4 Hz, 1H), 7.89 (s, 1H), 7.68 (s, 1H), 7.14-7.16 (m, 3H), 4.73 (brs, 1H), 4.23 (brs, 1H), 3.92-3.96 (m, 2H), 3.84 (brs, 1H), 3.63 (s, 3H), 3.25 (brs, 1H), 2.73 (brs, 1H), 2.40 (s, 3H), 2.36 (s, 3H
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([C:13]#[N:14])[CH3:12])[CH:6]=1)[CH3:2].[H-].[Na+].[CH3:18]I>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([C:13]#[N:14])([CH3:18])[CH3:12])[CH:6]=1)[CH3:2]
Reactant: CI
Reactant: CCOC(=O)c1cccc(C(C)C#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(C(C)(C)C#N)c1
Reaction time: 16 h

Procedure:
3-(1-Cyano-ethyl)-benzoic acid ethyl ester were dissolved in 4 ml dry DMF. Under nitrogen atmosphere, 138 mg of 60% sodium hydride and 423 mg methyl iodide were added at RT. The mixture was stirred for 16 hrs, then quenched by addition of 1 ml methanol and evaporated. The residue was purified by chromatography on silica in ethyl acetate/heptane mixtures.
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[N:20]=3)[CH:17]=2)[N:12]=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CCO.CCOC(C)=O>[F:31][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([F:32])[C:25]=1[C:21]1[N:20]=[C:19]([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[CH:11][CH:10]=[C:9]3[OH:8])[CH:24]=[CH:23][CH:22]=1
Reactant: Fc1cccc(F)c1-c1cccc(-c2ccc3nccc(OCc4ccccc4)c3c2)n1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Oc1ccnc2ccc(-c3cccc(-c4c(F)cccc4F)n3)cc12
Reaction time: 72 h
Yield: 70 %

Procedure:
To a solution of 4-(benzyloxy)-6-(6-(2,6-difluorophenyl)pyridin-2-yl)quinoline (1.0 equiv.) in 1:1 EtOH/EtOAc, at a concentration of 0.1 M, was added 10% palladium on carbon (0.1 eq.). The resultant heterogeneous solution was put under an atmosphere of hydrogen and was stirred for 72 hours. At this time the mixture was filtered through a pad of celite eluting with EtOAc. The volatiles were removed in vacuo yielding 6-(6-(2,6-difluorophenyl)pyridin-2-yl)quinolin-4-ol (70%). LCMS (m/z): 335.0 (MH+); LC Rt=3.09 min.