Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH2:15])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:24]=1[CH2:25]Br>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:24]=1[CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH2:15])=[O:14])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: NC(=O)c1cc(-c2ccc(O)cc2)no1
Reactant: Clc1cccc(Cl)c1CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccc(OCc3c(Cl)cccc3Cl)cc2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.4 %

Procedure:
3-(4-Hydroxy-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 2; 50 mg, 0.24 mmol), K2CO3 (37 mg, 0.27 mmol) and tetrabutylammonium iodide (9 mg, 0.024 mmol) were taken up in DMF (2.4 mL). 2,6-Dichlorobenzyl bromide (65 mg, 0.27 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by high-throughput purification to give 3-[4-(2,6-dichloro-benzyloxy)-phenyl]-isoxazole-5-carboxylic acid amide (8.2 mg, 9%). LRMS (ESI+): m/z [M+CH3CN+H]+ 404.0.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.[C@@H:19]12[CH2:25][C@@H:22]([CH2:23][CH2:24]1)[CH2:21][CH:20]2O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[C@@H:19]12[CH2:25][C@@H:22]([CH2:23][CH2:24]1)[CH2:21][CH:20]2[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Reactant: OC1C[C@@H]2CC[C@H]1C2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C[C@@]1(c2ccc3cc(OC4C[C@@H]5CC[C@H]4C5)ccc3c2)COC(=O)N1
Yield: 40 %

Procedure:
The compound was prepared in a manner similar as to that described above (R)-4-(6-hydroxynaphthalen-2-yl)-4-methyloxazolidin-2-one, (1S,4R)-Bicyclo[2.2.1]heptan-2-ol (1.0 g, 0.0090 mol), triphenylphosphine (2.6 g, 0.0099 mol), h (45 mL, 0.55 mol), and diisopropyl azodicarboxylate (2.0 g, 0.0099 mol) to give 502 mg of the desired product as a white solid (40%). 1H NMR (400 MHz, CDCl3) δ=7.94-7.61 (m, 3H), 7.50 (d, J=8.5 Hz, 1H), 7.23-7.05 (m, 2H), 4.67 (br. s., 2H), 4.33-4.17 (m, 1H), 3.84-3.51 (m, 2H), 2.49-0.78 (m, 11H).
Reaction SMILES: I[CH2:2][CH3:3].Cl.[NH:5]1[CH2:9][CH2:8][C@@H:7]([CH2:10][C:11]#[N:12])[CH2:6]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:2]([N:5]1[CH2:9][CH2:8][C@@H:7]([CH2:10][C:11]#[N:12])[CH2:6]1)[CH3:3]
Reactant: CCI
Reactant: N#CC[C@@H]1CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CC[C@@H](CC#N)C1
Yield: 51 %

Procedure:
Iodoethane (10.1 g) was added to a mixture of 2-((S)-pyrrolidin-3-yl)acetonitrile hydrochloride (Intermediate 205, 7.9 g) and potassium carbonate (29.7 g) in DMF (20 mL) and the resultant mixture was stirred at room temperature for 5 hours. Water was added and the mixture was extracted with ethyl acetate, washed with brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give 2-((S)-1-ethylpyrrolidin-3-yl)acetonitrile (3.8 g) as a yellow oil which was used without further characterisation.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([NH:14][CH2:15][CH2:16][N:17]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:11][C@@H:10]([C:28](=[O:48])[N:29]([CH:45]2[CH2:47][CH2:46]2)[CH2:30][C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])[CH:32]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@H:10]([C:28](=[O:48])[N:29]([CH:45]2[CH2:47][CH2:46]2)[CH2:30][C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])[CH:32]=2)[CH2:11][C@H:12]([NH:14][CH2:15][CH2:16][NH2:17])[CH2:13]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COCCCn1cc(CN(C(=O)[C@@H]2C[C@H](NCCN3C(=O)c4ccccc4C3=O)CN(C(=O)OC(C)(C)C)C2)C2CC2)c2ccccc21
Agent: NN
Solvent: CCO
Solvent: O
Product: COCCCn1cc(CN(C(=O)[C@@H]2C[C@H](NCCN)CN(C(=O)OC(C)(C)C)C2)C2CC2)c2ccccc21
Temperature: 60 °C
Reaction time: 6 h

Procedure:
A mixture of (3R*,5S*)-3-{Cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-5-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethylamino]-piperidine-1-carboxylic acid tert-butyl ester (160 mg, 0.24 mmol) and hydrazine monohydrate (18 uL, 0.37 mmol) in EtOH is stirred at 60° C. After 6 h, the reaction mixture is cooled down to room temperature. The solution is filtered through celite pad and the solvent is evaporated in vacuo to afford the title compound as yellow material. MS: 528 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 2.93 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[NH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.ClC1N=C(N2CCN(C(OC(C)(C)C)=O)CC2)C=NC=1>>[Cl:8][C:4]1[N:3]=[C:2]([NH:9][CH:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CC(C)(C)OC(=O)N1CCN(c2cncc(Cl)n2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2cncc(Cl)n2)CC1

Procedure:
tert-butyl 4-[(6-chloropyrazin-2-yl)amino]piperidine-1-carboxylate was prepared from 2,6-dichloropyrazine and tert-butyl 4-aminopiperidine-1-carboxylate using the conditions described for the preparation of tert-butyl 4-(6-chloropyrazin-2-yl)piperazine-1-carboxylate (Compound 1, Step 6). LRMS calculated for C14H21ClN4O2 [M+Na]+, 335.1; found 335.1.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[S:12][CH:13]=[C:14]([C:16]([NH2:18])=O)[N:15]=2)[N:9]=[C:8]([C:19]([F:22])([F:21])[F:20])[CH:7]=1.B.C1COCC1.B>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[S:12][CH:13]=[C:14]([CH2:16][NH2:18])[N:15]=2)[N:9]=[C:8]([C:19]([F:20])([F:21])[F:22])[CH:7]=1
Reactant: NC(=O)c1csc(-n2nc(C(F)(F)F)cc2-c2ccco2)n1
Agent: B
Solvent: C1CCOC1
Product: NCc1csc(-n2nc(C(F)(F)F)cc2-c2ccco2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.8 %

Procedure:
To a stirred suspension of 30 (317 mg, 0.966 mmol) in THF (966 μl) at 0° C. was added a solution of BH3.THF (1M in THF) (3.9 mL, 3.9 mmol). The resulting solution was allowed to stir for 4 h at room temperature. Then more borane.THF (1M in THF) (1 mL) was added. Stirring was continued for 16 h at room temperature. The mixture was quenched with methanol, and then solvent was evaporated to afford 31 (297 mg, 98%) as a yellow solid. LRMS (ESI): calc. 314.0; found 315.1 (MH)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.CCN(C(C)C)C(C)C.[CH3:24][N:25]1[CH:29]=[CH:28][C:27]([NH2:30])=[N:26]1>C1COCC1>[CH3:24][N:25]1[CH:29]=[CH:28][C:27]([NH:30][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=2)=[N:26]1
Reactant: Cn1ccc(N)n1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(SC)nc1Nc1ccn(C)n1
Yield: 81.3 %

Procedure:
To a solution of 800 mg of ethyl 4-chloro-2-(methylsulfanyl)pyrimidine-5-carboxylate in 20 mL of THF, 890 mg of DIPEA and 368 mg of 1-methyl-1H-pyrazol-3-amine were added, and the resulting mixture was stirred under reflux for 2 hours, and then, the solvent was distilled off. The thus obtained crude product was purified by silica gel column chromatography, whereby 820 mg the title compound was obtained.
Reaction SMILES: C([NH:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[CH2:14][O:15][CH:16]([CH2:25][O:26]C(=O)C(C)(C)C)[CH2:17][O:18]C(=O)C(C)(C)C)=[C:7](Cl)[N:6]=1)(=O)C.[NH3:34]>>[NH2:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[CH2:14][O:15][CH:16]([CH2:25][OH:26])[CH2:17][OH:18])=[C:7]([NH2:34])[N:6]=1
Reactant: CC(=O)Nc1nc(Cl)c2ncn(COC(COC(=O)C(C)(C)C)COC(=O)C(C)(C)C)c2n1
Reactant: N
Product: Nc1nc(N)c2ncn(COC(CO)CO)c2n1

Procedure:
A solution of 2-acetylamino-6-chloro-9-[1,3-di(2,2-dimethylpropanoyloxy)-2-propoxymethyl]purine (200 mg) in methanolic ammonia (15 ml) was heated in a Parr bomb at 90° C. for 18 hours. The solution was evaporated and the residue recrystallized from methanol to give 136 mg of 2,6-diamino-9-(1,3-dihydroxy-2-propoxymethyl)purine, m.p. 176°-177° C.
Reaction SMILES: II.Br[C:4]1[C:5]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1.[CH3:21][C:22](Cl)=[O:23].[NH4+].[Cl-]>C1COCC1>[CH2:10]1[O:9][C:8]2[C:7](=[CH:6][C:5]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:4]([C:22](=[O:23])[CH3:21])[CH:12]=2)[O:11]1
Reactant: Brc1cc2c(cc1OCc1ccccc1)OCO2
Reactant: CC(=O)Cl
Agent: II
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1cc2c(cc1OCc1ccccc1)OCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.6 %

Procedure:
In a flame-dried flask was added under argon Mg (0.58 g, 0.024 mol), a few crystals of I2 and dry THF (10 ml). A solution of 6-bromo-5-(phenylmethoxy)-1,3-benzodioxole (6.14 g, 0.02 mol) in dry THF (15 ml) was added dropwise under reflux. Heating was continued for 3 hours. The Grignard reagent was added over 1.5 h to a solution of freshly distilled CH3COCl (7 ml) in dry THF (20 ml) held at -78° C. The stirred reaction mixture was allowed to warm to room temperature overnight, poured into 2N-NH4Cl (100 ml) solution and extracted with chloroform (3×50 ml). The organic layer was washed with 10% NaOH and brine, and dried (MgSO4) and concentrated under reduced pressure. The residue was subjected to flash chromatography (silica gel) using petroleum ether--CHCl3 (2:1) as eluent affording 3.87 g (71.6%) of 1-[4,5-(methylenedioxy)-2-(phenylmethoxy)phenyl]ethanone mp (EtOH) 116.5°-117° C.; IR(KBr) 1652 (carbonyl) cm-1 ; NMR (CDCl3, 90 MHz) δ 2.55 (S, 3H, CH3), 5.11 (S, 2H, CH2Ph), 5.98 (S, 2H, OCH2O), 6.58 (S, 1H, ArH), 7.34 (S, 1H, ArH), 7.40 (S, 5H, CH2Ph). Anal. calcd. for C16H14O4 : C, 71.10; H, 5.22. Found: C, 70.96; H, 5.29.
Reaction SMILES: C(O)(=O)C.[C:5]([C:8]1[N:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=1)(=[NH:7])[NH2:6].C([O:20][C:21](=O)[CH:22]([Cl:26])[C:23]([CH3:25])=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[Cl:26][C:22]1[C:21]([OH:20])=[N:7][C:5]([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=2)=[N:6][C:23]=1[CH3:25]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CC(=O)Nc1ccc(C(=N)N)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(-c2nc(C)c(Cl)c(O)n2)nc1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
To a solution of compound of example 44 (0.01 g, 0.56 mmol) in water (2 mL) and ethanol (1 mL) was added ethyl-2-chloroacetoacetate (0.015 g, 0.89 mmol) and sodium carbonate (0.0107 g, 1.011 mmol). The reaction mixture was stirred at room temperature for a period of 26 hours. Ethanol was removed under reduced pressure, and the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography using silica gel and 1% methanol in chloroform as an eluent to obtain the title compound.
Reaction SMILES: [N:1]1[N:5]2[C:6]3[C:11]([C:12](O)=[CH:13][C:4]2=[N:3][N:2]=1)=[CH:10][CH:9]=[CH:8][N:7]=3.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:12]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[N:1]=[N:2][N:3]=[C:4]2[CH:13]=1
Reactant: Oc1cc2nnnn2c2ncccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cc2nnnn2c2ncccc12

Procedure:
Tetrazolo[1,5-a][1,8]naphthyridin-5-ol (0.5 g, 2.67 mmole) was suspended in phosphorous oxychloride (10 mL) and heated at reflux for 4 hours. The reaction mixture was concentrated under vacuum and the residue was poured into water. Dichloromethane was added and the aqueous layer was made basic with sodium bicarbonate. The dichloromethane layer was separated, dried over magnesium sulfate, filtered and then concentrated under vacuum. The resulting solid was recrystallized from toluene to provide 0.3 g of 5-chlorotetrazolo[1,5-a][1,8]naphthyridine as a solid, m.p. 229-230° C. (decomposition). Analysis: Calculated for C8H4ClN5: % C, 46.73; % H, 1.96; % N, 34.06; Found: % C, 46.87; % H 1.54; % N, 33.93.
Reaction SMILES: [NH2:1][C@H:2]([CH3:19])[C@:3]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C@@:3]([OH:10])([CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1)[C@H:2]([NH:1][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:19]
Reactant: CCOC(=O)CBr
Reactant: C[C@@H](N)[C@](O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Product: CCOC(=O)CN[C@H](C)[C@](O)(Cn1cncn1)c1ccc(Cl)cc1Cl

Procedure:
Following the procedure described in reference example 8, but starting from (2R*,3R*)-3-amino-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-dichlorophenyl)-2-butanol (obtained according to patent EP 332387) and using ethyl bromoacetate instead of benzyl bromoacetate, the title compound was obtained in a similar yield.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1)(=O)=O.[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:20]([CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1)=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](COS(C)(=O)=O)C1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](CN=[N+]=[N-])C1
Temperature: 80 °C
Reaction time: 4 h
Yield: 84.2 %

Procedure:
To a solution of 10.50 g of {(3S)-1-(tert-butoxycarbonyl)-3-piperidyl}methyl methanesulfonate in 100 ml of N,N-dimethylformamide, 4.9 g of sodium azide was added at room temperature, followed by 4 hours' stirring at 80° C. under heating. The reaction liquid was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and resulting residue was purified by means of silica gel column chromatography (eluting solvent: from hexane to hexane/ethyl acetate=15/1) to provide 7.24 g of the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.C([Mg]Cl)(C)C.[B:22](OC)([O:25]C)[O:23]C.C(OB1OC(C)(C)C(C)(C)O1)(C)C>>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:5]1[CH:6]=[CH:7][C:2]([B:22]([OH:25])[OH:23])=[CH:3][C:4]=1[C:13]([F:16])([F:15])[F:14]
Reactant: COB(OC)OC
Reactant: FC(F)(F)c1cc(I)ccc1C1OCCO1
Agent: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Product: OB(O)c1ccc(C2OCCO2)c(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
The title compound was prepared from 2-[4-iodo-2-(trifluoromethyl)phenyl]-1,3-dioxolane (Example I-IX-7) according to the procedure described for Example V-18, with the following exceptions: the aryl iodide and i-PrMgCl were aged 45 min before introduction of the electrophile (instead of 30 min); trimethyl borate was used as the electrophile (instead of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane); the dried organic extracts were concentrated to dryness and triturated with Et2O/hexanes (instead of flash chromatography). White solid. LC/MS (method A) 2.22 min, m/z 417 ({2[M−glycol]−H2O}−H, 23%), 217 ([M−glycol]−H, 57%), 189 (100%, −ve ion).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5](I)=[CH:4][C:3]=1[F:10].[CH2:11]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)[CH2:12][CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.O.C(O)C>[Br:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([C:19]2[CH:18]=[CH:17][C:16]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:21][CH:20]=2)=[C:6]([F:8])[CH:7]=1
Reactant: CCCCCc1ccc(B(O)O)cc1
Reactant: Fc1cc(I)c(F)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCc1ccc(-c2cc(F)c(Br)cc2F)cc1
Yield: 107.6 %

Procedure:
A mixture of 1-bromo-2,5-difluoro-4-iodbenzene (5.00 g, 15.68 mmol), 4-pentylphenylboronic acid (3.01 g, 15.67 mmol), potassium carbonate (3.25 g, 23.51 mmol), tetrabutylammonium bromide (1.26 g, 3.91 mmol), dichlorobis(triphenylphosphine)palladium (II) (0.55 g, 0.79 mmol), triphenylphosphine (0.41 g, 1.56 mmol), and a mixed solvent (toluene/water/ethanol=1/1/1, 100 ml) was refluxed for 32 hrs with stirring. The reaction mixture obtained was extracted with toluene (200 ml). The extract was washed with water (100 ml) twice and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure gave a brown oil (5.72 g). The oil was distilled under reduced pressure and was purified by silica-gel chromatography (eluent; heptane, Rf=0.58) to give a colorless oil (2.31 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1.[C:23](Cl)(=[O:26])[CH2:24][OH:25]>N1C=CC=CC=1>[C:24]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1)(=[O:25])[CH2:23][OH:26]
Reactant: O=C(Cl)CO
Reactant: O=C1Nc2ccc(O)cc2C1=Cc1ccnc2ccccc12
Solvent: c1ccncc1
Product: O=C(CO)Oc1ccc2c(c1)C(=Cc1ccnc3ccccc13)C(=O)N2
Temperature: 0 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
To a stirred solution of 5-hydroxy-3-(quinol-4-ylmethylene)-2-oxindole (2.883 g, 10 mmol) in pyridine (10 ml) was added gradually glycoloyl chloride (0.945 g, 10 mmol) at 0°-5° C. under cooling. The reaction mixture was stirred for about 4 h at 0°-5° C. and then for 15 h at room temperature. The mixture was poured onto an ice-water mixture, the precipitate filtered off, the residue washed thoroughly with water and then chromatographed on silica gel, using CHCl3 --MeOH mixtures as eluant. Thus pure title compound was obtained in about 60% yield.
Reaction SMILES: C([O:4][C@@H:5]([CH3:51])[C:6]([N:8]([CH2:34][C@H:35]1[C@@H:39]([F:40])[CH2:38][N:37](C(OCC2C=CC=CC=2)=O)[CH2:36]1)[C@@H:9]([C:14]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:17]=[C:16]([C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=2[F:33])[N:15]=1)[C:10]([CH3:13])([CH3:12])[CH3:11])=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O.CO.[Pd]>[CH2:19]([N:18]1[C:14]([C@H:9]([N:8]([CH2:34][C@H:35]2[C@@H:39]([F:40])[CH2:38][NH:37][CH2:36]2)[C:6](=[O:7])[C@@H:5]([OH:4])[CH3:51])[C:10]([CH3:13])([CH3:11])[CH3:12])=[N:15][C:16]([C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=2[F:33])=[N:17]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)O[C@@H](C)C(=O)N(C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F)[C@@H](c1nc(-c2cc(F)ccc2F)nn1Cc1ccccc1)C(C)(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@H](O)C(=O)N(C[C@@H]1CNC[C@@H]1F)[C@@H](c1nc(-c2cc(F)ccc2F)nn1Cc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
To a solution of (3R,4R)-benzyl 3-(((S)-2-acetoxy-N—((R)-1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)propanamido)methyl)-4-fluoropyrrolidine-1-carboxylate (1.78 g, 2.53 mmol) in degassed EtOAc (25 mL, 0.1 M solution) was added Pd/C (178 mg, 10 wt %) under anhydrous N2 atmosphere. After flushed with hydrogen gas, the reaction mixture equipped with a hydrogen gas balloon was stirred at room temperature for overnight. The reaction mixture was filtered through Celite® pad that was washed with EtOAc. The volatile organic filtrate was removed in vacuo to give the crude amine (LC/MS (uplc): MH+ 572.4, 1.11 min). Then, the crude product was dissolved in MeOH (168 mL, 0.015 M solution) followed by addition of anhydrous potassium carbonate (3.5 g, 25 mmol). The reaction was then stirred for 15 min at room temperature. After white precipitate was removed by filtration, the organic filtrate was concentrated in vacuo. The crude product was purified by preparative reverse phase HPLC. The combined fractions of the product were neutralized with saturated NaHCO3 solution, which was then extracted with EtOAc (200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The dried product was then dissolved in acetonitrile and water (1:1 ratio) and lyophilized for 48 h. The white powdery (S)—N—((R)-1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)-N-(((3S,4R)-4-fluoropyrrolidin-3-yl)methyl)-2-hydroxypropanamide was obtained in 65.5% yield (876 mg, over 3 steps) as a free amine 1H NMR (CD3Cl, 400 MHz): 7.82 (1H, m), 7.52 (2H, m), 7.34-7.25 (3H, m), 7.16 (1H, m), 7.07 (1H, m), 6.09 (1H, s), 5.44 (2H, s), 4.61 (2H, m), 4.39 (1H, m), 3.78 (1H, m), 3.60 (1H, m), 2.92 (1H, m), 2.56 (1H, m), 2.16 (2H, m), 1.44 (3H, m), 1.22 (1H, m), 0.99 (9H, s), 0.42 (1H, m). LC/MS (uplc): MH+ 530.3, 1.05 min.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[C:6]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C:3]=1[C:4]#[N:5].[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[N:9]=[C:8]([CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)[CH:7]=[C:6]([C:15]2[CH:16]=[CH:17][C:18]([O:21][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH3:31])=[CH:19][CH:20]=2)[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(-c2ccc(O)cc2)cc(C2CCCC2)nc1Cl
Reactant: Cc1ccccc1B(O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: Cc1ccccc1Oc1ccc(-c2cc(C3CCCC3)nc(Cl)c2C#N)cc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 57.6 %

Procedure:
A mixture of 2-chloro-6-cyclopentyl-4-(4-hydroxyphenyl)nicotinonitrile (20 mg, 0.067 mmol, product A from Step 4 of Example 2), o-tolylboronic acid (36.4 mg, 0.268 mmol), copper(II) acetate (14.59 mg, 0.080 mmol) and 4 A molecular sieves (100 mg) in dichloromethane (3 mL) was stirred at room temperature while opening to the air for 40 h. The mixture was filtered through a CELITE® pad and the pad rinsed with ethyl acetate (50 mL). The filtrate was washed with saturated sodium bicarbonate (5 mL), water (5 mL), brine (5 mL), dried (MgSO4) and concentrated. Silica gel chromatography, eluting with 0-15% ethyl acetate in hexanes, gave 2-chloro-6-cyclopentyl-4-(4-(o-tolyloxy)phenyl)nicotinonitrile as a colorless liquid (15 mg, 58% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.50 (2H, δ, J=8.53 Hz), 7.07-7.32 (5H, m), 6.91-7.03 (2H, m), 3.05-3.28 (1H, m), 2.20 (3H, s), 1.98-2.13 (2H, m), 1.60-1.91 (6H, m); MS (ES+) m/z: 389 (M+H); LC retention time: 4.578 min (analytical HPLC Method A).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH2:3][C:4]([CH3:8])([CH3:7])[CH2:5][NH2:6].[C:10](O)(=[O:13])[CH:11]=[CH2:12]>B(F)(F)F>[CH3:1][N:2]([CH3:9])[CH2:3][C:4]([CH3:8])([CH3:7])[CH2:5][NH:6][C:10](=[O:13])[CH:11]=[CH2:12]
Reactant: C=CC(=O)O
Reactant: CN(C)CC(C)(C)CN
Agent: FB(F)F
Product: C=CC(=O)NCC(C)(C)CN(C)C
Yield: 72 %

Procedure:
Proceeding as in Example 1, 260 g 3-dimethylamino-2,2-dimethylpropylamine; 144 g acrylic acid; 4 g N,N'-diphenylenediamine; and 10 ml BF3-etherate were mixed. It was found possible to isolate 265 g (72%) of the N-(3-dimethylamino-2,2-dimethylpropyl)acrylamide.