Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[O:14][CH3:15].[F:16][C:17]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[CH:19][C:18]=1[Si:32]([CH3:35])([CH3:34])[CH3:33].[F-].[K+].CC#N>C(Cl)Cl.O.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>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:21]2[CH:20]=[CH:19][C:18]([Si:32]([CH3:34])([CH3:33])[CH3:35])=[C:17]([F:16])[CH:22]=2)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[O:14][CH3:15]
Reactant: CC1(C)OB(c2ccc([Si](C)(C)C)c(F)c2)OC1(C)C
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc([Si](C)(C)C)c(F)c2)c(F)c(N)c1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53.3 %

Procedure:
To a 5-mL microwave safe vial were added methyl 4-amino-6-chloro-5-fluoro-3-methoxypicolinate (0.400 g, 1.705 mmol), (2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)trimethylsilane (0.690 g, 2.344 mmol), KF (0.297 g, 5.11 mmol), and PdCl2(PPh3)2 (0.120 g, 0.170 mmol). A mixture of H2O (1 mL) and CH3CN (2 mL) was added, and the reaction vial was capped and placed in a Biotage Initiator microwave reactor for 20 min at 115° C. with external infrared (IR)-sensor temperature monitoring from the side of the vessel. Upon cooling to room temperature, the reaction mixture was diluted with CH2Cl2 (25 mL) and H2O (25 mL), and the organic layer was filtered through a cotton plug. An additional extraction using EtOAc (25 mL) was combined with the CH2Cl2 and dried over Na2SO4 (50 g). Following filtration of the combined organics through a cotton plug and concentration on a rotary evaporator, the residue was purified using a Teledyne ISCO purification system with a gradient eluent system of CH2Cl2 and EtOAc to yield the title compound as a light pink oil (333 mg, 53%): 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J=7.6 Hz, 1H), 7.55 (d, J=9.8 Hz, 1H), 7.46 (dd, J=7.6, 5.9 Hz, 1H), 4.57 (s, 2H), 3.98 (s, 3H), 3.96 (s, 3H), 0.33 (s, 9H); 19F NMR (376 MHz, CDCl3) δ −100.72, −140.12; ESIMS m/z 367 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH:10]2[CH:15]([C:16]([OH:18])=O)[CH2:14][CH:13]=[CH:12][CH2:11]2)=[CH:4][CH:3]=1.Cl.[NH2:20][CH2:21][C:22]#[N:23].F[P-](F)(F)(F)(F)F.N1([PH+](N2CCCC2)N2CCCC2)CCCC1.C(N(CC)CC)C>CN(C)C=O>[C:21]([CH2:22][NH:23][C:16]([CH:15]1[CH:10]([CH2:9][S:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:11][CH:12]=[CH:13][CH2:14]1)=[O:18])#[N:20]
Reactant: N#CCN
Reactant: O=C(O)C1CC=CCC1CSc1ccc(F)cc1
Agent: C1CCN([PH+](N2CCCC2)N2CCCC2)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCNC(=O)C1CC=CCC1CSc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 28 h

Procedure:
(1R/S,6R/S)-6-{[(4-Fluorophenyl)sulfanyl]methyl}cyclohex-3-ene-1-carboxylic acid (620 mg, 2.34 mmol) was weighed into a 25 mL round bottom flask and aminoacetonitrile hydrochloride (480 mg, 5.20 mmol) and benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (1.34 g, 2.60 mmol) were added. Dimethylformamide (8.0 mL) was added and the reaction mixture was cooled to 0° C. After adding triethylamine (1.2 mL, 8.6 mmol) the reaction mixture was stirred at ambient temperature for 28 h, and then partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated. Chromatography of the residue on silica gel with 45:55 ethyl acetate:hexanes eluent provided the title compound as a colorless solid. 1H NMR (500 MHz, acetone-d6): δ=7.92 (1H, br s), 7.41 (2H, dd), 7.08 (2H, dd), 5.64 (2H, m), 4.24 (2H, m), 3.22 (1H, dd), 2.72 (1H, dd), 2.50-2.40 (2H, m), 2.26-2.20 (2H, m), 2.12 (1H, m), 1.86 (1H, m). MS [ESI, (M−H)−] m/z=303.1 amu.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH2:14][NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CCN(C(C)C)C(C)C.[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH2:14][N:13]([C:32](=[O:33])[CH2:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NNCC2)cc1OC
Reactant: O=C(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2=NN(C(=O)Cc3ccccc3)CC2)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 19 %

Procedure:
A scintillation vial equipped with a stir bar was charged with 3-(3,4-dimethoxy-phenyl)-4,5-dihydro-1H-pyrazole (412 mg, 2 mmol), Hunigs base (1 mL, 6 mmol) and dry CH2Cl2 (10 mL). To this mixture was added phenyl-acetyl chloride, (0.27 mL, 2 mmol) and the reaction was stirred at RT for 3 h. LC-MS indicated consumption of SM. The mixture was diluted with CH2Cl2 (50 mL) and added to water (50 mL). The phases were separated and the CH2Cl2 phase was washed with saturated Na2CO3, (50 mL), dried (Na2SO4) and the solvent was evaporated under reduced pressure. The material was purified using a 40 g silica cartridge eluting with heptane-EtOAc, gradient 0 to 100% EtOAc. Amount obtained: 123 mg, 0.37 mmol, 19% yield. LC-MS (ESI) m/e 325 (M+H). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.21 (t, J=10.03 Hz, 2H) 3.94 (s, 3H) 3.98 (s, 3H) 4.04 (t, J=10.03 Hz, 2H) 4.11 (s, 2H) 6.90 (d, J=8.35 Hz, 1H) 7.16 (dd, J=8.27, 1.88 Hz, 1H) 7.21-7.26 (m, 1H) 7.31 (t, J=7.42 Hz, 2H) 7.40-7.44 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:40][N:41]([C@@H:58]([C:66](=[O:74])[NH:67][CH2:68][CH:69]1[CH2:73][CH2:72][CH2:71][O:70]1)[CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:42](=[O:57])[C@H:43]([NH:55][CH3:56])[CH2:44][C:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47][CH:46]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](=[O:15])[N:55]([CH3:56])[C@@H:43]([C:42](=[O:57])[N:41]([CH3:40])[C@@H:58]([C:66](=[O:74])[NH:67][CH2:68][CH:69]1[CH2:73][CH2:72][CH2:71][O:70]1)[CH2:59][C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)[CH2:44][C:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47][CH:46]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Reactant: CN[C@H](Cc1cccc2ccccc12)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)NCC1CCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C)[C@H](Cc1cccc2ccccc12)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)NCC1CCCO1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.2 %

Procedure:
(2E)-5-(tert-Butoxycarbonylamino)-5-methylhex-2-enoic acid (0.344 g; 1.41 mmol) was dissolved in methylene chloride (10 mL). 1-Hydroxy-7-azabenzotriazole (0.19 g; 1.41 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.298 g; 1.56 mmol) were added. The reaction mixture was stirred for 15 min at room temperature. (2R)-N-Methyl-2-methylamino-3-(1-naphthyl)-N-((1R)-2-phenyl-1-(((tetrahydrofuran-2-yl)methyl)carbamoyl)ethyl)-propionamide (0.67 g; 1.42 mmol) was dissolved in methylene chloride (10 mL) and added. Diisopropyletylamine (0.242 mL; 1.41 mmol) was added. The reaction mixture was stirred for 12 hours at room temperature. Methylene chloride (20 mL) was added. The reaction mixture was washed with water (30 mL), an aqueous solution of sodium hydrogen sulfate (10%; 30 mL), an aqueous solution of sodium hydrogen carbonate (pH 8; 30 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was chromatographed on silica (3×30 cm) using methylene chloride/ethyl acetat (1:1) as eluent to afford 0.81 g of ((3E)-1,1-dimethyl-4-(methyl-((1R)-1-(methyl-((1R)-2-phenyl-1-(((tetrahydrofuran-2-yl)methyl)carbamoyl)ethyl)carbamoyl)-2(1-naphtyl)ethyl)-carbamoyl)but-3-enyl)carbamic acid tert butylester.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[S:8]/[C:9]/1=[N:10]\[C:11]([CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1)=[O:12])[CH2:2][CH2:3][CH3:4].[CH2:22]([O:24][C:25](Cl)=[O:26])[CH3:23]>>[CH2:1]([C:5]1=[CH:6][N:7]([C:18]([CH3:20])([CH3:19])[CH3:21])[S:8]/[C:9]/1=[N:10]\[C:11]([CH:13]1[CH2:17][CH2:16][N:15]([C:25]([O:24][CH2:22][CH3:23])=[O:26])[CH2:14]1)=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1CCNC1
Reactant: CCOC(=O)Cl
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1CCN(C(=O)OCC)C1

Procedure:
The product from Example 104B and ethylchloroformate (Aldrich) were processed using the method described in Example 102 to afford the title compound. 1H NMR (DMSO-d6) δ ppm 0.91 (t, J=7.3 Hz, 3H), 1.18 (t, J=6.9 Hz, 3H), 1.24-1.37 (m, 3H), 1.51-1.64 (m, 3H), 1.58 (s, 9H), 2.05-2.14 (m, 2H), 2.61-2.66 (m, 2H), 3.21-3.28 (m, 1H), 3.49-3.64 (m, 2H), 4.02 (q, J=7.1 Hz, 2H), 8.57 (s, 1H). (ESI+) m/z 410 (M+H)+.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Cl.O=[C:7]([CH3:31])[CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]([CH3:30])[C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:17]2[C:22]=1[CH:21]=[CH:20][C:19]([Cl:23])=[CH:18]2)=[O:13].C([BH3-])#N.[Na+]>CO>[ClH:23].[CH:1]([NH:4][CH:7]([CH3:31])[CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]([CH3:30])[C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:17]2[C:22]=1[CH:21]=[CH:20][C:19]([Cl:23])=[CH:18]2)=[O:13])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CC(=O)CCCNC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)NC(C)CCCNC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5.2 ml. of isopropylamine in 25 ml. of methanol is treated with 4 ml. of 5-N methanolic hydrochloric acid. Thereafter, there are successively added under an atmosphere of argon at 20°-25° C. 3.7 g. of 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid(4-oxopentyl)amide and 0.4 g. of sodium cyanoborohydride and the mixture is then stirred at room temperature for 48 hours. The mixture is made acidic with concentrated hydrochloric acid while cooling with ice, stirred at room temperature for an additional 0.5 hour and then concentrated to dryness under reduced pressure. The residue is made alkaline with 0.5-N sodium hydroxide with the addition of ice and extracted with 200 ml. of diethyl ether. The extract, dried over sodium sulfate, is concentrated to dryness and the residual oily base crystallized from hot hexane. The thus-obtained colorless base, which melts at 102°-105° C. is dissolved in 30 ml. of acetone and treated with excess ethereal hydrochloric acid. The separated hydrochloride is removed by filtration and washed with acetone, and there is obtained 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid [4-(isopropylamino)pentyl]amide hydrochloride in the form of colorless crystals having a melting point of 216°-218° C. (decomposition). Recrystallization from acetone/methanol does not increase the melting point.
Reaction SMILES: C(O[C:4](=[O:15])[C:5]([CH3:14])([CH3:13])[C:6]([C:8]1[O:9][CH:10]=[CH:11][CH:12]=1)=O)C.[NH:16]([C:18]1[CH:37]=[CH:36][C:21]([C:22]([NH:24][CH:25]2[CH2:30][C:29]([CH3:32])([CH3:31])[N:28]([CH3:33])[C:27]([CH3:35])([CH3:34])[CH2:26]2)=[O:23])=[CH:20][CH:19]=1)[NH2:17]>C(O)(=O)C>[O:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[C:6]1[C:5]([CH3:13])([CH3:14])[C:4](=[O:15])[N:16]([C:18]2[CH:37]=[CH:36][C:21]([C:22]([NH:24][CH:25]3[CH2:26][C:27]([CH3:34])([CH3:35])[N:28]([CH3:33])[C:29]([CH3:32])([CH3:31])[CH2:30]3)=[O:23])=[CH:20][CH:19]=2)[N:17]=1
Reactant: CCOC(=O)C(C)(C)C(=O)c1ccco1
Reactant: CN1C(C)(C)CC(NC(=O)c2ccc(NN)cc2)CC1(C)C
Solvent: CC(=O)O
Product: CN1C(C)(C)CC(NC(=O)c2ccc(N3N=C(c4ccco4)C(C)(C)C3=O)cc2)CC1(C)C

Procedure:
3-Furan-2-yl-2,2-dimethyl-3-oxo-propionic acid ethyl ester (53 mg) and 4-Hydrazino-N-(1,2,2,6,6-pentamethyl-piperidin-4-yl)-benzamide (85 mg) in 0.5 ml of acetic acid were heated up at 65° C. for 2 h. Concentration in vacuo and purification by HPLC gave the expected product (MH+: 451.4)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:37]([F:40])([F:39])[F:38])[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][C:29](=[O:31])[NH:28][C:27](=[O:32])[CH2:26]4)=[O:24])=[C:19]([C:33]([F:36])([F:35])[F:34])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.I[CH2:42][CH2:43][CH3:44].C(=O)([O-])[O-].[K+].[K+].CC#N>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:37]([F:40])([F:38])[F:39])[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:26][C:27](=[O:32])[N:28]([CH2:42][CH2:43][CH3:44])[C:29](=[O:31])[CH2:30]4)=[O:24])=[C:19]([C:33]([F:36])([F:35])[F:34])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=C1CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(C(F)(F)F)c4)(C(F)(F)F)C3)cc2C(F)(F)F)CC(=O)N1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCCN1C(=O)CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(C(F)(F)F)c4)(C(F)(F)F)C3)cc2C(F)(F)F)CC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 25-mL round-bottom flask, was placed a solution of 4-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)phenyl)carbonyl]piperazine-2,6-dione (70 mg, 0.12 mmol, 1.00 equiv) in N,N-dimethylformamide (2 mL), 1-iodopropane (32 mg, 0.19 mmol, 2.00 equiv), potassium carbonate (59 mg, 0.43 mmol, 3.00 equiv). The resulting solution was stirred for 2 h at 25° C. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 2×10 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2). This resulted in 31 mg (41%) of 4-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)phenyl)carbonyl]-1-propylpiperazine-2,6-dione as a white solid. (ES, m/z): [M+CH3CN]+ 685.0; 1H NMR (300 MHz, CDCl3): δ 7.79-7.84 (m, 2H), 7.73-7.87 (m, 3H), 7.46 (d, J=7.8 Hz, 1H), 4.86 (d, J=19.4 Hz, 1H), 4.56 (d, J=18.3 Hz, 1H), 4.19 (d, J=17.4 Hz, 1H), 4.05 (s, 2H), 3.75-3.81 (m, 3H), 1.52-1.64 (m, 2H), 0.93 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH3:9])[CH:3]=1.[F:10]OC(=O)C>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH3:9])[C:3]=1[F:10]
Reactant: CC(=O)OF
Reactant: Cc1cc(Cl)c(F)cn1
Product: Cc1ncc(F)c(Cl)c1F

Procedure:
4-Chloro-5-fluoro-2-picoline is treated with 1.1 equivalents of acetyl hypofluorite as described by O. Lerman, et al. J Org Chem, 49:806-813 (1984) to afford the title compound.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10]([CH:12]=O)[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][NH:15][CH:16]1[C:25]2[N:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Na+].[Cl-]>ClCCCl.C(O)(=O)C>[CH3:14][N:15]([CH2:12][C:10]1[N:9]=[N:8][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:11]=1)[CH:16]1[C:25]2[N:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:19][CH2:18][CH2:17]1
Reactant: CNC1CCCc2cccnc21
Reactant: O=Cc1cn(-c2ccccc2)nn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(Cc1cn(-c2ccccc2)nn1)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-phenyl-1H-1,2,3-triazole-4-carbaldehyde, 9, (0.23 g, 1.35 mmol) in 1,2-dichloroethane (2 mL) was added N-methyl-5,6,7,8-tetrahydroquinolin-8-amine, 5, (0.20 g, 1.23 mmol), sodium triacetoxyborohydride (0.10 g, 1.60 mmol), and 3 drops of acetic acid. The reaction mixture was stirred for 16 h at room temperature. The reaction mixture was then poured into aqueous saturated NaCl (10 mL) and was extracted with ethyl acetate (10 mL). The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-5% methanol/dichloromethane) yielding 35 mg (9%) of Y: 1H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 8.47 (s, 1H), 7.78, (d, J=8.4 Hz, 2H), 7.50-7.39, (m, 4H), 7.20, (m, 1H), 4.72, (d, J=13.6 Hz, 1H), 4.63-4.58 (m, 2H), 2.90-2.60 (m, 6H), 2.22-2.17 (m, 1H), 2.10-1.95, (m, 1H), 1.90-1.78, (m, 1H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:16](C(OCC(Cl)(Cl)Cl)=O)[CH2:15][CH:14]4[CH2:25][CH2:26][CH2:27][N:13]4[C:12](=[O:28])[C:11]=3[CH:29]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+].C(OCC)(=O)C>C1COCC1>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:16]=[CH:15][C@@H:14]4[CH2:25][CH2:26][CH2:27][N:13]4[C:12](=[O:28])[C:11]=3[CH:29]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CC2CCCN2C(=O)c2cc(-c3ccccc3)ccc21
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1c2cc(-c3ccccc3)ccc2N=C[C@@H]2CCCN12
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
Cd/Pb (0.47 g) couple was added portion wise to a vigorously stirred solution of 135 (0.33 g, 0.7 mmol) in THF (5 mL) and of aq. ammonium acetate (1M, 5 mL). The suspension was allowed to stir at room temperature for 2 hours, then poured into ethyl acetate (200 mL), dried with MgSO4 and filtered. The filtrate was evaporated and the residue purified by flash column chromatography (ethyl acetate) to afford the title compound as colourless oil (0.19 g, 98%): 1H NMR (270 MHz, CDCl3) δ2.0-2.12 (m, 2H); 2.29-2.37 (m, 2H); 3.53-3.63 (m, 1H); 3.76-3.92 (m, 2H); 7.36-7.79 (m, 8H); 8.28 (d, J=2.2 Hz, 1H). 13C NMR (67.8 MHz, CDCl3) δ24.4; 29.8; 46.9; 53.8; 126.9; 127.3; 127.7; 128.0; 128.2; 128.8; 128.9; 129.1; 130.1; 130.5; 139.5; 145.0; 164.5; 165.1. IR (Nujol): cm−1 3000-2800, 1620, 1455, 1377, 1239, 1239, 1014, 990, 761,728, 697. HRMS Calculated for C18H16N2O: 276.1261. Found: 276.1262. [α]25D=+131.4° (c=0.19, CHCl3).
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][N+:9]([O-])=[CH:8][CH:7]=1.C(OC(=O)C)(=[O:20])C>>[F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][NH:9][C:8](=[O:20])[CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: [O-][n+]1ccc(OCc2ccc(F)cc2F)cc1
Product: O=c1cc(OCc2ccc(F)cc2F)cc[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
A solution of 4-(2,4-difluorobenzyloxy)pyridine-1-oxide (13.4 g, 57 mmol) in acetic anhydride (30 mL) was stirred at reflux for 4 h. The solvent was removed under reduced pressure, the residue was diluted with 1:1 MeOH/water (60 mL), and the mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure. Purification by flash column chromatography (silica, eluent methylene chloride to 9:1 methylene chloride/methanol) provided 4-(2,4-difluorobenzyloxy)-1H-pyridin-2-one as a light brown solid (4.2 g, 31%): 1H NMR (300 MHz, CDCl3) δ 7.43 (q, J=8 Hz, 1H), 7.23 (d, J=7 Hz, 1H), 6.91-6.87 (m, 2H), 6.02 (dd, J=8, 2 Hz, 1H), 5.97 (d, J=2 Hz, 1H), 5.03 (s, 2H).
Reaction SMILES: Br/[C:2](/[C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:18][CH2:17]2)=[C:12]([O:19][CH3:20])[N:11]=1)=[CH:3]\[C@@H:4]1[NH:8][C:7](=[O:9])[CH2:6][CH2:5]1.[Cl:21][C:22]1[CH:23]=[C:24](OB(O)O)[CH:25]=[CH:26][C:27]=1[Cl:28].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O.O1CCOCC1>[CH:16]1([C:13]2[CH:14]=[CH:15][C:10](/[C:2](/[C:25]3[CH:24]=[CH:23][C:22]([Cl:21])=[C:27]([Cl:28])[CH:26]=3)=[CH:3]/[C@@H:4]3[NH:8][C:7](=[O:9])[CH2:6][CH2:5]3)=[N:11][C:12]=2[O:19][CH3:20])[CH2:18][CH2:17]1
Reactant: OB(O)Oc1ccc(Cl)c(Cl)c1
Reactant: COc1nc(/C(Br)=C/[C@H]2CCC(=O)N2)ccc1C1CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(Cl)c(Cl)c2)ccc1C1CC1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
1,4-Dioxane (4 mL) and water (0.5 mL) were added to a mixture of (5R)-5-[(Z)-2-bromo-2-(5-cyclopropyl-6-methoxypyridin-2-yl)ethenyl]pyrrolidin-2-one (300 mg), 3,4-dichlorophenylboric acid (340 mg), tris(dibenzylideneacetone)dipalladium (81 mg), tri(2-furyl) phosphine (124 mg) and cesium carbonate (867 mg), and the mixture was stirred at 90° C. for three hours. Water and ethyl acetate were added to the reaction solution and the insoluble matter was filtered off through celite, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:50→0:100) to give (5R)-5-[(E)-2-(5-cyclopropyl-6-methoxypyridin-2-yl)-2-(3,4-dichlorophenyl)ethenyl]pyrrolidin-2-one as a colorless amorphous (250 mg, 69%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:12]([O-])=[O:13].[Na+].C(OCC)=O>C(O)C.C(O)(=O)/C=C/C(O)=O>[CH:12]([NH:11][NH:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)=[O:13]
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: O=C[O-]
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC=O
Product: O=CNNc1ccc([N+](=O)[O-])cc1

Procedure:
4-Nitrophenylhydrazine (9.2 g, 0.06 mole), sodium formate (4.08 g, 0.06 mole), and ethyl formate (148 g, 2.00 moles) were mixed in ethanol (40 ml) and fumaric acid (30 ml). The mixture was heated on a steam bath; the volume of the mixture was reduced to approximately 100 ml by continued boiling. The hydrazide product crystallized out of the concentrated reaction mixture upon cooling. The product was filtered off, washed with ethanol, and dried. Yield 10.2 g (94%), m.p. 183°-185° C.
Reaction SMILES: OC1C=CC(C2C=CC(O)=CC=2)=CC=1.[OH-].[K+].CC(CC)CBr.[CH3:23][C@@H:24]([CH2:45][CH3:46])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36]([O:39]C[C@@H](C)CC)=[CH:35][CH:34]=2)=[CH:29][CH:28]=1.Cl>C(O)C>[OH:39][C:36]1[CH:35]=[CH:34][C:33]([C:30]2[CH:31]=[CH:32][C:27]([O:26][CH2:25][C@@H:24]([CH3:23])[CH2:45][CH3:46])=[CH:28][CH:29]=2)=[CH:38][CH:37]=1
Reactant: CC[C@H](C)COc1ccc(-c2ccc(OC[C@@H](C)CC)cc2)cc1
Agent: CCC(C)CBr
Agent: Cl
Agent: Oc1ccc(-c2ccc(O)cc2)cc1
Solvent: CCO
Product: CC[C@H](C)COc1ccc(-c2ccc(O)cc2)cc1

Procedure:
A mixture of 4,4'-dihydroxybiphenyl (500 g), ethyl alcohol (7.5 l) and potassium hydroxide (302 g) was heated with stirring under reflux, and (+)-2-methylbutylbromide (prepared from (-)-2-methylbutanol and phosphorus bromide) (530 g) was dropwise added to carry out reaction for 4 hours, followed by distilling off ethanol, adding water (2 l), filtering, collecting insoluble matter, adding toluene to this insoluble matter to dissolve and remove toluene-soluble matter (this soluble matter, when recrystallized from ethyl alcohol, gave scaly crystals having a m.p. of 80.5° C.; thus the compound was confirmed to be 4,4'-di((S)-2-methylbutyloxy)biphenyl), heating the insoluble matter together with 3N-hydrochloric acid with stirring, cooling solid matter and recrystallizing from toluene and then from ethyl alcohol to obtain 4-hydroxy-4'-((S)-2-methylbutyloxy)biphenyl (XXI) having a m.p. of 137.5° C. (125 g).