Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([S:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:20]3[CH:25]=[C:24]([F:26])[C:23]([CH:27]([F:29])[F:28])=[CH:22][C:21]=3[O:30][CH3:31])=[N:14][C:15]([CH3:19])=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.CC(O)=O.[OH2:36].[Cl:37]N1C(C)(C)C(=O)N(Cl)C1=O.[OH2:48]>C(Cl)Cl>[F:28][CH:27]([F:29])[C:23]1[C:24]([F:26])=[CH:25][C:20]([C:13]2[C:12]3[C:17](=[CH:18][C:9]([S:8]([Cl:37])(=[O:48])=[O:36])=[CH:10][CH:11]=3)[N:16]=[C:15]([CH3:19])[N:14]=2)=[C:21]([O:30][CH3:31])[CH:22]=1
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Reactant: COc1cc(C(F)F)c(F)cc1-c1nc(C)nc2cc(SCc3ccccc3)ccc12
Reactant: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(C(F)F)c(F)cc1-c1nc(C)nc2cc(S(=O)(=O)Cl)ccc12
Reaction time: 0.25 h
Yield: 58.4 %

Procedure:
A solution of 7-(benzylthio)-4-(4-(difluoromethyl)-5-fluoro-2-methoxyphenyl)-2-methylquinazoline (0.995 g, 2.259 mmol) in 22 mL DCM and 0.44 mL (3:2 HOAc/water) solution was cooled to 0° C. and was treated with 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.890 g, 4.52 mmol). After stirring for 15 minutes, LC/MS showed mostly product, so the reaction mixture was diluted with water. The layers were separated, and the organics were dried over MgSO4 and concentrated. Purification of the crude residue by silica gel column chromatography (0-75% EtOAc/heptane) gave 4-(4-(difluoromethyl)-5-fluoro-2-methoxyphenyl)-2-methylquinazoline-7-sulfonyl chloride (0.550 g, 1.320 mmol, 58.4% yield) white solid. (M+H)+=417.0.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]([C:11]1[CH:12]=[C:13]([Mg]Br)[CH:14]=[CH:15][CH:16]=1)=[CH2:10]>>[CH:9]([C:11]1[CH:12]=[C:13]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=[CH:15][CH:16]=1)=[CH2:10]
Reactant: C=Cc1cccc([Mg]Br)c1
Reactant: ClCc1ccccc1
Product: C=Cc1cccc(Cc2ccccc2)c1

Procedure:
The method using benzyl chloride as a starting material is described. Benzyl chloride is reacted with a Grignard reagent of 3-vinylphenylmagnesium bromide in the presence of dichlorodiphosphine nickel complex catalyst to obtain (3-vinylphenyl)phenylmethane. The reaction temperature using Grignard reagent is in the range of 10° to 80° C. and the use quantity of Grignard reagent is 1.0 to 1.2 equivalent to 1 mole of benzyl chloride. ##STR8##
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]2[CH2:19][CH2:20][N:21]=[C:3]12.[C:22]([NH:29][C@H:30]([C:38](O)=[O:39])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.C(N(CC)CC)C>[C:25]([O:24][C:22]([NH:29][C@@H:30]([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:38]([NH:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]2[CH2:19][CH2:20][N:21]=[C:3]12)=[O:39])=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: NC1N=C(c2ccccc2)c2ccccc2N2CCN=C12
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NC1N=C(c2ccccc2)c2ccccc2N2CCN=C12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Crude 4(R,S)-amino-2,4-dihydro-6-phenyl-1H-imidazo-[1,2-a]-[1,4]-benzodiazepine (1.37 g), Boc-L-phenyl-alanine (1.37 g, 5.17 mmole), 1-hydroxybenzotriazole (0.07 g, 5.17 mmole), and 1-ethyl-3-(3-dimethylaminopropyl)carbodimide hydrochloride (0.99 g, 5.17 mmole) are combined in DMF (30 mL) and stirred at room temperature. The pH of the reaction mixture is adjusted to 8.5 with triethylamine, and after 1/2 hour, the DMF is removed in vacuo, and the residue partitioned between ethyl acetate and 10% citric acid solution (10 mL). The layers are separated and the organic phase is washed with sodium bicarbonate solution (NaHCO3, saturated). The combined organic layers are washed with brine, dried over Na2SO4, filtered, and evaporated to dryness in vacuo to give the title compound as a mixture of diastereomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]3[CH2:12][CH2:13][C:14](=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]3=[CH:6][C:5]=2[C:4]=1[CH3:21]>CCOC(C)=O.C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]3[CH2:12][CH2:13][CH:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]3=[CH:6][C:5]=2[C:4]=1[CH3:21]
Reactant: CCOC(=O)C=C1CCn2c1cc1c(C)c(OC)ccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CC1CCn2c1cc1c(C)c(OC)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
Ethyl 2-(7-methoxy-8-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-ylidene)acetate (351 mg, 1.23 mmol) was dissolved in EtOAc (6 mL) and ethanol (6 mL), 10% Palladium on carbon (120 mg) was added. The reaction was degassed and charged with hydrogen, then stirred at room temperature overnight. The solid was filtered off. The filtrate was concentrated to give the title compound (320 mg) as an oil without further purification. LCMS m/z=288.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.32 (t, J=7.1 Hz, 3H), 2.25-2.32 (m, 1H), 2.40 (s, 3H), 2.58 (dd, J=16.0 and 8.6 Hz, 1H), 2.80-2.95 (m, 2H), 3.73-3.80 (m, 1H), 3.85 (s, 3H), 3.95-4.02 (m, 1H), 4.06-4.18 (m, 1H), 4.18-4.26 (m, 2H), 6.11 (s, 1H), 6.84 (d, J=8.6 Hz, 1H), 7.02 (d, J=8.6 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.S(NN)(C1C=CC(C)=CC=1)(=O)=O.CC([O-])=O.[Na+]>COCCOC.O>[Br:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1
Reactant: Brc1cnc(N2CCOCC2)c2nc(/C=C/c3ccc4ccccc4n3)cn12
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Brc1cnc(N2CCOCC2)c2nc(CCc3ccc4ccccc4n3)cn12
Temperature: 80 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
To a solution of compound 2b (5.00 g, 10.9 mmol, as prepared in Example 2, Step B) in DME/H2O (10:1 v/v, 150 mL) was added TosNHNH2 (6.41 g, 34.5 mmol) and NaOAc (4.70 g, 57.3 mmol). The reaction mixture was stirred at 80° C. overnight. After cooling to rt, the reaction was quenched with H2O (200 mL). The solids were collected by filtration and washed with Et2O to obtain compound 3a as a white solid (3.50 g, 67% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C21H20BrN5O: 438.1 (M+H). found: 438.1.
Reaction SMILES: [CH2:1]=[N:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:10].ClC([O:14][C:15](Cl)(Cl)Cl)=O.[CH:19]([NH:22][C:23]([NH:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[S:24])([CH3:21])[CH3:20].[OH-].[Na+]>>[C:26]([N:25]=[C:23]1[N:22]([CH:19]([CH3:21])[CH3:20])[C:15](=[O:14])[N:2]([C:3]2[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:10])[CH2:1][S:24]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: C=Nc1c(C)cccc1C
Reactant: CC(C)NC(=S)NC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc(C)c1N1CSC(=NC(C)(C)C)N(C(C)C)C1=O
Yield: 9 %

Procedure:
Similarly, 2.7 g (0.02 mole) of N-methylene-2,6-dimethylaniline, 2.0 g (0.01 mole) of trichloromethyl chloroformate, 3.3 g (0.019 mole) of 1-isopropyl-3-t-butylthiourea, and 18 g of a 10% aqueous sodium hydroxide solution were used to obtain 0.3 g (7% yield) of 2-t-butylimino-3-isopropyl-5-(2,6-dimethylphenyl)tetrahydro-1,3,5-thiadiazin-4-one (compound No. 388) of the formula, ##STR180## as white crystals melting at 103°-104° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12](O)[CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(Br)(Br)(Br)[Br:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.CCCCC>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH:12]([Br:16])[CH3:13])[CH:3]=1
Reactant: CC(O)c1cc(Br)cc(C(F)(F)F)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(Br)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (±)-1-(3-bromo-5-(trifluoromethyl)phenyl)ethanol (390 mg, 1.45 mmol) and carbon tetrabromide (577 mg, 1.74 mmol) in tetrahydrofuran (2 mL) at 0° C. was added triphenylphosphine (456 mg, 1.74 mmol). The resulting solution was stirred at room temperature for 2 h. The reaction was treated with an additional portion of carbon tetrabromide (289 mg, 0.87 mmol)) and triphenylphosphine (228 mg, 0.87 mmol). The reaction was stirred at room temperature for 1 h, diluted with several volumes of pentane, and filtered to remove undissolved solids. The organics were concentrated and purified by column chromatography (1→3% ethyl acetate/hexanes) to give 439 mg (91%) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ ppm 7.76 (s, 1H), 7.68 (s, 1H), 7.60 (s, 1H), 5.12 (q, J=7.0 Hz, 1H), 2.03 (d, J=7.0 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ ppm 146.4, 133.5, 132.9 (q, J=32.6 Hz), 128.4 (q, J=3.8 Hz), 123.0, 123.0 (q, J=273 Hz), 122.6 (q, J=3.8 Hz), 46.1, 26.6.
Reaction SMILES: Br[C:2]1[CH:40]=[CH:39][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:28][C:29]2([C:34]([O:36]CC)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:4][CH:3]=1.[CH3:41][S:42]([C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1)(=[O:44])=[O:43]>>[CH3:41][S:42]([C:45]1[CH:50]=[CH:49][C:48]([C:2]2[CH:40]=[CH:39][C:5]([CH2:6][N:7]3[C:11]4[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]5[CH:27]=[CH:26][C:25]6[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=6)[N:19]=5)=[CH:15][C:10]=4[N:9]=[C:8]3[CH2:28][C:29]3([C:34]([OH:36])=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33]3)=[CH:4][CH:3]=2)=[CH:47][CH:46]=1)(=[O:44])=[O:43]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(Br)cc2)CCCC1
Product: CS(=O)(=O)c1ccc(-c2ccc(Cn3c(CC4(C(=O)O)CCCC4)nc4cc(OCc5ccc6ccccc6n5)ccc43)cc2)cc1

Procedure:
The title compound was prepared using similar methods to those in Example 110 using ethyl 1-((1-(4-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)cyclopentanecarboxylate and 4-(methylsulfonyl)phenyl boronic acid in Step A. MS (ESI): mass calcd. for C38H35N3O5S, 645.23; m/z found, 646.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.22-8.18 (m, 1H), 8.10-8.06 (m, 1H), 8.00-7.96 (m, 2H), 7.85-7.80 (m, 1H), 7.76-7.72 (m, 1H), 7.72-7.67 (m, 3H), 7.57-7.52 (m, 3H), 7.46-7.41 (m, 1H), 7.18-7.14 (m, 1H), 7.14-7.10 (m, 2H), 7.08-7.03 (m, 1H), 5.42 (s, 2H), 5.39 (s, 2H), 4.15-4.04 (m, 1H), 3.09 (s, 3H), 2.27-2.19 (m, 3H), 2.05 (s, 2H), 1.77-1.68 (m, 2H), 1.28-1.24 (m, 1H), 1.00-0.91 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16]NC2C=CC(S(C)(=O)=O)=CC=2)=[CH:12][CH:11]=1.[NH2:29][C:30]1[C:31]([C:39](=[O:41])[CH3:40])=[CH:32][C:33]2[O:37][CH2:36][O:35][C:34]=2[CH:38]=1.[C:42](C1C=CC(C(O)=O)=CC=1)(=O)C>>[C:39]([C:31]1[C:30]([NH:29][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([C:9]([NH:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH2:1])=[O:28])=[CH:15][CH:14]=2)[CH3:42])=[CH:38][C:34]2[O:35][CH2:36][O:37][C:33]=2[CH:32]=1)(=[O:41])[CH3:40]
Reactant: CC(=O)c1cc2c(cc1N)OCO2
Reactant: CS(=O)(=O)c1ccc(NCc2ccc(C(=O)Nc3ccccc3N)cc2)cc1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: CC(=O)c1cc2c(cc1NC(C)c1ccc(C(=O)Nc3ccccc3N)cc1)OCO2

Procedure:
Title compound 240 was prepared using the same procedures as described for the compound 212a, example 99 (scheme 42, table 1), starting from 1-(6-amino-benzo[1,3]dioxol-5-yl)-ethanone and 4-acetylbenzoic acid (scheme 51). 1H NMR: (DMSO-d6) δ(ppm): 8.69 (s, 1H), 7.03 (d, J=7.8 Hz, 2H), 6.64 (d, J=7.8 Hz, 2H), 6.29 (dd, J=8.3, 7.8 Hz, 1H), 6.09 (t, J=7.8, 7.3 Hz, 1H), 5.90 (d, J=7.8, 1H), 5.72 (d, J=6.8 Hz, 1H), 5.70 (s, 1H), 5.16 (d, J=8.8 Hz, 1H), 4.88 (s, 1H), 4.84 (s, 1H), 4.07 (bd, 1H), 2.30 (s, 3H), 0.62 (d, J=6.83, 3H).
Reaction SMILES: Br[Mg][C:3]1[S:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)#N.CC[O:19]CC>>[Cl:8][C:5]1[S:4][C:3]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:19])=[CH:7][CH:6]=1
Reactant: N#Cc1ccccn1
Reactant: CCOCC
Reactant: Clc1ccc([Mg]Br)s1
Product: O=C(c1ccccn1)c1ccc(Cl)s1
Reaction time: 2 h
Yield: 52 %

Procedure:
To an etheral solution of bromo(5-chloro-2-thienyl)magnesium (prepared from 2-bromo-5-chloro-thiophene (1.9 g, 9.62 mmol) and magnesium turnings (234 mg, 9.62 mmol) in ether (20 ml)) was dropwise added a solution of 2-cyanopyridine (1 g, 9.62 mmol) in ether (10 ml) at room temperature. After 2 hours, the reaction was quenched by addition of an aqueous saturated solution of NH4Cl. The mixture was extracted with ether. The organic phase was dried over MgSO4 and concentrated under vacuum. The residue was treated with a 2 N HCl solution at 90° C. during 30 minutes. The solution was neutralized by addition of a concentrated solution of NaOH and extracted with ether. The organic phase was dried over MgSO4 and concentrated under vacuum. The residue was purified by chromatography on silica gel (hexane/AcOEt 90/10) to give the (5-chloro-2-thienyl)(2-pyridinyl)methanone 8 as a yellowish oil (1.13 g, 52%).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH:4]([CH2:24][CH:25]=[CH:26][CH2:27][P:28]([O:32][CH3:33])([O:30][CH3:31])=[O:29])[CH2:5][C:6]([CH3:23])=[CH:7][CH2:8][C:9]1[C:10]([OH:22])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21].O.CO.O[Li].O>C1COCC1>[CH3:31][O:30][P:28]([CH2:27][CH:26]=[CH:25][CH2:24][CH:4]([CH2:5][C:6]([CH3:23])=[CH:7][CH2:8][C:9]1[C:10]([OH:22])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21])[C:3]([OH:34])=[O:2])([O:32][CH3:33])=[O:29]
Reactant: COC(=O)C(CC=CCP(=O)(OC)OC)CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(C)c2c(c(O)c1CC=C(C)CC(CC=CCP(=O)(OC)OC)C(=O)O)C(=O)OC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-[4-(Dimethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoic acid methyl ester (460 mg, 0.927 mmol) in a solution of 1:1:2 of H2O, MeOH, THF (8 mL) was stirred with LiOH.H2O (78 mg, 1.86 mmol) at ambient temperature for 12 hours. A second batch of LiOH.H2O (40 mg, 0.952 mmol) was added. The reaction mixture was stirred at room temperature for another 16 hours, after which no further progress was observed. The reaction was quenched by addition of a saturated aqueous solution of NH4Cl. The organic layer was removed in vacuo and the product was extracted with EtOAc from the aqueous layer, which had been acidified by addition of 5 drops of 2 N HCl. The product was further purified by chromatography to provide the desired product. 1H NMR (300 MHz, CDCl3) δ 1.79 (s, 3H), 2.08-2.38 (m, 4H), 2.15 (s, 3H), 2.53 (d, 1H, J=22 Hz), 2.60 (d, 1H, J=22 Hz), 2.57-2.64 (m, 1H), 3.38 (d, 2H, J=7 Hz), 3.72 (d, 6H, J=11 Hz) 3.76 (s, 3H), 5.20 (s, 2H), 5.27 (t, 1H, J=6 Hz), 5.36-5.63 (m, 2H) ppm; 31P (121.4 MHz, CDCl3) δ 30.5 ppm; MS (m/z) 481.2 [M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:15]=1)[NH:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[N:30]=[CH:31][N:32]=[C:33]([NH2:36])[C:34]=2[N:35]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:15]=[C:14]([C:26]2[CH:27]=[CH:28][C:29]3[N:30]=[CH:31][N:32]=[C:33]([NH2:36])[C:34]=3[N:35]=2)[CH:13]=[C:4]([NH:5][CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][CH2:11][CH2:12]2)[CH:3]=1
Reactant: CC1(C)OB(c2cc(F)cc(NCCN3CCCC3)c2)OC1(C)C
Reactant: Nc1ncnc2ccc(Cl)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncnc2ccc(-c3cc(F)cc(NCCN4CCCC4)c3)nc12
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A suspension of crude 31-B (300 mg, 1.0 mmol), 3-A (150 mg, 0.80 mmol), Pd(PPh3)4 (30 mg) and Cs2CO3 (600 mg, 1.8 mmol) in dioxane/H2O (10 mL/1.0 mL) was stirred at 90° C. for 2 h. The reaction solution was partitioned between EtOAc (100 mL) and brine (35 mL). The combined organic layer was washed with water (3×30 mL), concentrated and purified by prep-HPLC (25 mg, 8.9%). LCMS (0-60AB), RT=0.904 min, M+H 352.9 1H-NMR (Methanol-d4, 400 MHz): δ 8.53 (s, 1H), 8.35 (s, 1H), 8.23 (d, J=8.8 Hz, 1H), 8.03 (d, J=8.8 Hz, 1H)), 7.33 (s, 1H), 7.24 (d, J=10.4 Hz, 1H), 6.49 (d, J=11.2 Hz, 1H), 3.60-3.57 (m, 2H), 3.37-3.28 (m, 6H), 2.07-2.04 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:12]O)=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.S(Cl)([Cl:16])=O>C(Cl)Cl>[Cl:16][CH2:12][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[C:5]([C:8]([F:11])([F:10])[F:9])[N:4]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(C(F)(F)F)nc1CO
Solvent: ClCCl
Product: Cc1ccc(C(F)(F)F)nc1CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3-methyl-6-(trifluoromethyl)pyridin-2-yl)methanol (29) (0.18 g, 0.94 mmol) in DCM (5 ml) was added thionyl chloride (0.112 g, 0.95 mmol) and stirred at rt for 2 h. After completion of the reaction, mixture was concentrated and washed with hexane to afford 2-(chloromethyl)-3-methyl-6-(trifluoromethyl)pyridine (30). The crude solid was taken directly for the next step (180 mg, 91.8%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])[C:9]1=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.S(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH:13]([CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)[OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)C2CCCC2)C1=O
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)(C)OC(=O)N1CCC(C(O)C2CCCC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.3 %

Procedure:
3-Cyclopentanecarbonyl-2-oxopyrrolidine-1-carboxylic acid t-butyl ester (1.2 g, 4.4 mmol) was dissolved in THF (3.5 mL, 43.7 mmol) under nitrogen. 2M BH3.Me2S in THF (6.6 mL, 13.1 mmol) was added via syringe over 15 minutes. The mixture was stirred at room temperature for 1 hour, then heated at 65° C. for 24 hours. After an additional 48 hours, the mixture was placed on an ice bath and the reaction slowly quenched with cold MeOH (100 mL). The mixture was stirred for 15 minutes, then diluted with EtOAc (30 mL), and washed with saturated aqueous NaHCO3 (2×50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated by rotary evaporation to yield a yellow oil (300 mg). The oil was purified by preparative HPLC (2″ column; 5-50% MeCN/H2O; 0.1% TFA buffer; at 40 mL/min over 80 minutes). The desired fractions were collected, frozen and lyophilized to yield the title compound (939 mg). MS in/z: [M+H]+ calcd for C15H27NO3, 269.3. found 270.4.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[Mg].C([C@@H]1CC[C@@H](C)C[C@H]1O[C:22](=[O:36])[C:23]([O:25][C@@H:26]1[CH2:31][C@H:30]([CH3:32])[CH2:29][CH2:28][C@H:27]1[CH:33]([CH3:35])[CH3:34])=[O:24])(C)C.[NH4+].[Cl-]>C1COCC1.CCCCCCC.CCOCC>[O:36]=[C:22]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1)[C:23]([O:25][C@@H:26]1[CH2:31][C@H:30]([CH3:32])[CH2:29][CH2:28][C@H:27]1[CH:33]([CH3:34])[CH3:35])=[O:24]
Reactant: C=Cc1ccc(Br)cc1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=Cc1ccc(C(=O)C(=O)O[C@@H]2C[C@H](C)CC[C@H]2C(C)C)cc1
Temperature: 25 °C
Yield: 47.1 %

Procedure:
A Grignard reagent prepared from 4-bromostyrene (2.75 g, 15.0 mmol) and magnesium (0.39 g, 16.0 mmol) in THF (20 mL) was added dropwise (during a period of 20 min) to a stirred solution of bis[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)oxalate (5.00 g, 13.7 mmol) in THF (15 mL) at −60° C. The mixture was left warming to room temperature and poured into a mixture of ice (200 g) and a saturated solution of NH4Cl (10 mL). Extraction with diethyl ether (2×), washing with water (3×), drying (Na2SO4) and concentrating afforded 6.42 g of the crude compound as an oil. Repetitive column chromatography (SiO2, heptane/ether 7:3 and heptane/ether 95:5) gave 2.03 g (47%) of an oil.
Reaction SMILES: [CH2:1]([O:4][P:5]([O:11][CH2:12][C:13]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:14]=1[C:15]([O:17]CC1C=CC(OC)=CC=1)=[O:16])([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:2]=[CH2:3].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[CH2:8]([O:7][P:5]([O:11][CH2:12][C:13]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:14]=1[C:15]([OH:17])=[O:16])([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH:9]=[CH2:10]
Reactant: C=CCOP(=O)(OCC=C)OCc1cccc(F)c1C(=O)OCc1ccc(OC)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C=CCOP(=O)(OCC=C)OCc1cccc(F)c1C(=O)O

Procedure:
According to a similar procedure to that described in Example 4-(6), 4-methoxybenzyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]-6-fluorobenzoate (1.07 g, 2.39 mmol) obtained from Example 9-(1) was reacted with anisole (1.8 g, 16.6 mmol) and trifluoroacetic acid (5 ml), and the reaction mixture was worked up to afford 2[[bis(allyloxy)phosphoryl]oxymethyl]-6-fluorobenzoic acid as a crude product.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:11]=[C:10]([CH:12]([CH3:16])[CH2:13][CH2:14][OH:15])[CH:9]=[CH:8][C:7]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[C:1]([O:15][CH2:14][CH2:13][CH:12]([C:10]1[CH:9]=[CH:8][C:7]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:6]([Cl:5])[CH:11]=1)[CH3:16])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(CCO)c1ccc(-c2ccccc2)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)OCCC(C)c1ccc(-c2ccccc2)c(Cl)c1
Temperature: 100 °C
Yield: 80 %

Procedure:
A solution of 3.92 gm (0.05 mol) of acetyl chloride in 20 ml of absolute toluene was allowed to flow into a solution of 10.0 gm (0.038 mol) of 3-(2-chloro-4-biphenylyl)-1-butanol and 5.0 gm (0.05 mol) of triethylamine in 100 ml of absolute toluene at room temperature; the resulting mixed solution was then stirred for several hours and was subsequently heated for 1 hour at 100°C. Thereafter, the reaction mixture was allowed to cool, water was then added, the toluene phase was separated, and the aqueous phase was extracted with ether. The combined organic solutions were washed until neutral, dried and evaporated, and the residue was distilled in vacuo, yielding 9.21 gm (80% of theory) of the desired ester in the form of a colorless oil having a boiling point of 145°-152°C at 0.06 mm Hg.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:11][CH2:10][O:9][CH2:8][C:7]=1[S:12]([OH:15])(=O)=[O:13])=[O:5])[CH3:2].S(Cl)([Cl:18])=O>>[Cl:18][S:12]([C:7]1[CH2:8][O:9][CH2:10][CH2:11][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5])(=[O:15])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C1=C(S(=O)(=O)O)COCC1
Product: CCOC(=O)C1=C(S(=O)(=O)Cl)COCC1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
4-(Ethoxycarbonyl)-5,6-dihydro-2H-pyran-3-sulfonic acid (27.5 g) was dissolved in thionyl chloride (82.6 ml) and the mixture was stirred at room temperature→85° C. for 3 h. The reaction mixture was concentrated to dryness under reduced pressure and the residue was dissolved in ethyl acetate (100 ml). The obtained solution was partitioned by adding diluted brine (120 ml). The ethyl acetate layer was washed twice with saturated brine (50 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent:ethyl acetate/hexane=1/7→1/5). The objective product was concentrated under reduced pressure and the crystals produced by freezing were washed with hexane to give ethyl 5-(chlorosulfonyl)-3,6-dihydro-2H-pyran-4-carboxylate (7.81 g) as pale-yellow crystals.