Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1CC[CH2:6][CH:5](CCN2C(OC)=NC3C2=NC(O[C@@H](C)CCC)=NC=3N)[CH2:4]1)C.[CH3:29][C@H:30]([O:34][C:35]1[N:43]=[C:42]2[C:38]([N:39]=[C:40]([O:52][CH3:53])[N:41]2[CH2:44][CH2:45][CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[C:37]([NH2:54])[N:36]=1)[CH2:31][CH2:32][CH3:33].IC(C)C>>[CH3:29][C@H:30]([O:34][C:35]1[N:43]=[C:42]2[C:38]([N:39]=[C:40]([O:52][CH3:53])[N:41]2[CH2:44][CH2:45][CH:46]2[CH2:47][CH2:48][N:49]([CH:5]([CH3:6])[CH3:4])[CH2:50][CH2:51]2)=[C:37]([NH2:54])[N:36]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCN(CC)C3)c2n1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCNCC3)c2n1
Solvent: CC(C)I
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCN(C(C)C)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 46 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9-[2-(4-piperidinyl)ethyl]-9H-purin-6-amine and 2-iodopropane. LCMS (System B): tRET=1.27 min; MH+ 405
Reaction SMILES: C(N)C1C=CC=CC=1.[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1.[CH:18]1([CH2:21][N:22]2[CH2:26][CH2:25][N:24]([C:27]3[CH:28]=[C:29]([CH:34]=[CH:35][N:36]=3)[C:30](OC)=[O:31])[C:23]2=[O:37])[CH2:20][CH2:19]1>>[CH:18]1([CH2:21][N:22]2[CH2:26][CH2:25][N:24]([C:27]3[CH:28]=[C:29]([CH:34]=[CH:35][N:36]=3)[C:30]([NH:15][CH2:14][C:13]3[CH:16]=[CH:17][C:10]([F:9])=[CH:11][CH:12]=3)=[O:31])[C:23]2=[O:37])[CH2:20][CH2:19]1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1ccnc(N2CCN(CC3CC3)C2=O)c1
Solvent: NCc1ccccc1
Product: O=C(NCc1ccc(F)cc1)c1ccnc(N2CCN(CC3CC3)C2=O)c1
Yield: 77 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace benzylamine with 4-fluorobenzylamine to react with methyl 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)isonicotinate, 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-N-(4-fluorobenzyl)isonicotinamide was obtained as a colorless solid in 77% yield: mp 150-151° C.; 1H NMR (300 MHz, CDCl3) δ 8.53 (s, 1H), 8.34 (d, J=5.4 Hz, 1H), 7.39 (d, J=5.4 Hz, 1H), 7.30-7.24 (m, 2H), 7.01-6.91 (m, 3H), 4.55 (d, J=5.7 Hz, 2H), 4.06 (t, J=8.1 Hz, 2H), 3.59 (t, J=8.1 Hz, 2H), 3.13 (d, J=7.2 Hz, 2H), 99-0.85 (m, 1H), 0.59-0.51 (m, 2H), 0.24-0.19 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 165.7, 163.9, 160.6, 156.9, 153.1, 148.0, 133.6, 133.6, 129.8, 129.7, 115.9, 115.7, 115.4, 108.9, 48.6, 43.4, 41.6, 41.5, 9.0, 3.4; MS (ES+) m/z 369.3 (M+1).
Reaction SMILES: [Cl:1][C:2](Cl)=[CH:3][C:4]([CH3:7])([CH3:6])[CH3:5].[C:9]1([O-:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Na+]>CN(C)C=O>[Cl:1][CH:2]=[C:3]([O:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)C=C(Cl)Cl
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=CCl)Oc1ccccc1
Yield: 98 %

Procedure:
16.5 g (0.108 mols) of 1,1-dichloro-3,3-dimethyl-1-butene are heated under reflux with 23.2 g (0.2 mol) of sodium phenolate in 100 ml of dimethylformamide, during the course of 12 hours. The customary working-up according to Example A1(a) yields, with distillation at a boiling point of 80° C./0.5 mm Hg, 22.3 g of 1-chloro-3,3-dimethyl-2-phenoxy-1-butene.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].COC(=O)CC1CC2C(=CC(OCCCCNC(N)=N)=CC=2)NC1=O.C[O:34][C:35](=[O:59])[CH2:36][C:37]1[C:38](=[O:58])[N:39]([CH2:56][CH3:57])[C:40]2[C:45]([CH:46]=1)=[CH:44][CH:43]=[C:42]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][NH:52][C:53]([NH2:55])=[NH:54])[CH:41]=2>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:56]([N:39]1[C:40]2[C:45](=[CH:44][CH:43]=[C:42]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][NH:52][C:53]([NH2:55])=[NH:54])[CH:41]=2)[CH:46]=[C:37]([CH2:36][C:35]([OH:59])=[O:34])[C:38]1=[O:58])[CH3:57]
Reactant: CCn1c(=O)c(CC(=O)OC)cc2ccc(OCCCCNC(=N)N)cc21
Agent: COC(=O)CC1Cc2ccc(OCCCCNC(=N)N)cc2NC1=O
Solvent: O=C(O)C(F)(F)F
Product: CCn1c(=O)c(CC(=O)O)cc2ccc(OCCCCNC(=N)N)cc21

Procedure:
The title compound is prepared using the procedure of Example 84 except that [7-(4-guanidino-butoxy)-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]acetic acid methyl ester trifluoroacetate is replaced with [1-ethyl-7-(4-guanidino-butoxy)-2-oxo-1,2-dihydro-quinolin-3-yl]acetic acid methyl ester.
Reaction SMILES: S(Cl)(Cl)=O.Cl.C(OC([N:13]1[CH2:18][CH:17]=[C:16]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([OH:24])=[O:23])[CH2:15][CH2:14]1)=O)(C)(C)C.[CH3:28]O>>[NH:13]1[CH2:18][CH:17]=[C:16]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([O:24][CH3:28])=[O:23])[CH2:15][CH2:14]1
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(C(=O)O)c2)CC1
Agent: Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(C2=CCNCC2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Thionyl chloride (2.39 mL, 32.7 mmol) was added dropwise to 15 mL of anhydrous methanol. The resulting anhydrous methanolic HCl solution was added to 3-[1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]benzoic acid (3.31 g, 10.9 mmol) and the reaction mixture was stirred at rt for 6 h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica, 5-10% stepwise gradient in 1% increments of 10% NH4OH (28% solution)/methanol in DCM) to give methyl 3-(1,2,3,6-tetrahydropyridin-4-yl)benzoate. ESI-MS calc. for C13H15NO2: 217; Found: 218 (M+H).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][CH:9]([F:37])[CH2:10][NH:11][C:12]1[N:13]=[C:14]2[CH2:36][CH2:35][NH:34][CH2:33][C:15]2=[N:16][C:17]=1[N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH2:20][CH2:19]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:71][O:72][C@H:73]([CH3:77])[C:74](O)=[O:75]>CN(C=O)C>[F:37][CH:9]([F:8])[CH2:10][NH:11][C:12]1[N:13]=[C:14]2[CH2:36][CH2:35][N:34]([C:74](=[O:75])[C@H:73]([O:72][CH3:71])[CH3:77])[CH2:33][C:15]2=[N:16][C:17]=1[N:18]1[CH2:19][CH2:20][CH:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH2:22][CH2:23]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CO[C@H](C)C(=O)O
Reactant: Fc1ccc(OC2CCN(c3nc4c(nc3NCC(F)F)CCNC4)CC2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@H](C)C(=O)N1CCc2nc(NCC(F)F)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2C1
Reaction time: 8 h

Procedure:
A solution of N-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (17 mg, 0.032 mmol), DIPEA (12.2 mg, 0.095 mmol), and HATU (13.2 mg, 0.035 mmol) in DMF (158 μL) was stirred for 10 min at rt. To this was added (R)-2-methoxypropanoic acid (3.6 mg, 0.035 mmol), and the resulting reaction mixture stirred overnight. The crude reaction mixture was diluted in DMF, filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR), and purified via HPLC Method A to give the title compound as a TFA salt (6 mg) as a clear oil. 1H NMR (400 MHz, methanol-d4, mixture of rotamers) δ ppm 1.32 (d, J=6.8 Hz, 1.3H), 1.38 (d, J=6.6 Hz, 1.7H), 1.92-2.03 (m, 2H), 2.09-2.18 (m, 2H), 2.78 (t, J=6.2 Hz, 0.9H), 2.86 (m, 1.1H), 2.97-3.06 (m, 2H), 3.33 (s, 3H), 3.35-3.43 (m, 2H), 3.79 (td, J=14.5, 4.3 Hz, 2H), 3.85-3.97 (m, 2H), 4.36 (dq, J=12.7, 6.5 Hz, 1H), 4.42-4.49 (m, 1H), 4.58 (m, 0.9H), 4.68 (m, 1.1H), 5.90-6.22 (m, 1H), 6.84-6.91 (m, 1H), 6.98 (ddd, J=11.4, 8.5, 3.0 Hz, 1H), 7.18 (td, J=9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]+ 512.4.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].I>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2ccc(Sc3ccccc3)cc2c1O
Agent: I
Product: CCCCOC(=O)c1ncc2ccc(Sc3ccccc3)cc2c1O
Yield: 34 %

Procedure:
540 mg of 1-bromo-4-hydroxy-6-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (1.25 mmol) were reacted with red phosphorous and HI analogously to Example D-1 f). The crude product was purified by flash column chromatography on silica gel eluting with hexanes:ethyl acetate (85:15). 150 mg of the title compound were obtained; 1H NMR (CDCl3): δ=11.78 (s, 1 H), 8.71 (d, 1 H), 8.11 (t, 1 H), 7.79 (d, 1 H), 7.39 to 7.54 (m, 6 H), 4.49 (t, 2 H), 1.87 (m, 2 H), 1.47 (m, 2 H), 0.98 (t, 3 H).
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6]([P:9](=[O:12])([O-:11])[O-])=[C:5](C2C=CC=CC=2Br)[C:4]=1[C:20]([F:23])([F:22])[F:21])C.O1[CH2:28][CH2:27][CH2:26][CH2:25]1.[C:29]([Li])(C)([CH3:31])[CH3:30]>CCCCC>[F:23][C:20]([F:21])([F:22])[C:4]1[CH:5]=[C:6]([P:9]2(=[O:12])[C:27]3[CH:28]=[CH:30][CH:29]=[CH:31][C:26]=3[CH2:25][O:11]2)[CH:7]=[CH:8][CH:3]=1
Reactant: C1CCOC1
Reactant: CCc1ccc(P(=O)([O-])[O-])c(-c2ccccc2Br)c1C(F)(F)F
Reactant: [Li]C(C)(C)C
Solvent: CCCCC
Product: O=P1(c2cccc(C(F)(F)F)c2)OCc2ccccc21
Temperature: -76 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
Under a nitrogen atmosphere a solution of ethyl-2-bromophenyl-3-trifluoromethylphenylphosphonate (2.4 g, 0.00567 mole) in 50 ml. of tetrahydrofuran was cooled to -76° C. in a solid carbon dioxide-acetone bath. To this cooled solution was dropwise added a solution of t-butyllithium (0.74 g, 0.0116 mole) in 6.1 ml. of pentane at a rate such that the temperature of the reaction was maintained below -65° C. The reaction mixture was then stirred for one hour at -76° C. after which time the temperature of the reaction mixture was allowed to rise to 26° C. over a period of 45 minutes. The reaction was quenched with the addition of 1 ml. of acetic acid. The reaction mixture was concentrated to yield a yellow residue which was partitioned between methylene chloride and water. The methylene chloride layer was dried over magnesium sulfate and concentrated in vacuo to yield a yellow glass-like residue. The glass-like residue was distilled to yield a colorless oil which was crystallized upon trituration in petroleum ether to yield 1-[3-(trifluoromethyl)phenyl]-1,3-dihydro-2,1-benzoxaphosphole-1-oxide (0.85 g, 51% yield) as a white solid having a melting point of 102°-106° C. and the following analysis:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[C:4]([C:10]2[NH:14][N:13]=[N:12][N:11]=2)[N:3]=1.I[CH3:16].[C:17](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[C:4]([C:10]2[N:14]([CH3:17])[N:13]=[N:12][N:11]=2)[N:3]=1.[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[C:4]([C:10]2[NH:14][N:13]([CH3:16])[NH:12][N:11]=2)[N:3]=1
Reactant: CI
Reactant: O=C([O-])[O-]
Reactant: Clc1cc(-c2nnn[nH]2)nc(Cl)c1Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1NN=C(c2cc(Cl)c(Cl)c(Cl)n2)N1
Product: Cn1nnnc1-c1cc(Cl)c(Cl)c(Cl)n1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 2,3,4-trichloro-6-(1H-tetrazol-5-yl)pyridine (3.25 g, 13 mmol), iodomethane (1.84 g, 13 mmol), and potassium carbonate (1.79 g, 13 mmol) in dimethylformamide (100 mL) was stirred at 25° C. for 22 hours. The volatiles were removed and the residue purified by column chromatography (15% ethyl acetate in hexane) to provide 2,3,4-trichloro-6-(1-methyl-1H-tetrazol-5-yl)pyridine (1.66 g, 6.3 mmol), mp 138-141° C. and 2,3,4-trichloro-6-(2-methyl-1H-tetrazol-5-yl)pyridine (1.05 g, 4.0 mmol), mp 156-157° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Br)[N:5]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[C:21]1(OB(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.C1COCC1.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:5]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:3]=1
Reactant: OB(O)Oc1ccccc1
Reactant: CC(=O)Nc1cc(N)c(C#N)c(Br)n1
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: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(N)c(C#N)c(-c2ccccc2)n1
Temperature: 130 °C
Yield: 72.7 %

Procedure:
A mixture of bromide from Example 65A (45 mg, 0.18 mmol), Na2CO3 (38 mg, 0.35 mmol), and Pd(PPh3)4 (10 mg, 0.009 mmol) was stirred in DMF/THF/H2O (1:1:0.5) under nitrogen in a microwave reactor vial. Phenyl boric acid (26 mg, 0.21 mmol) was added. The resulting mixture was capped and heated at 130° C. for 20 min in a microwave reactor. The crude mixture was partitioned between EtOAc and water. The organic layer washed with water and brine, dried over Na2SO4, and evaporated under reduced pressure. The crude residue was purified by a Gilson reverse phase HPLC to provide the titled compound (33 mg, 72% yield). 1H NMR (300 MHz, d6-DMSO) δ 10.44 (s, 1H), 7.74-7.68 (m, 2H), 7.55 (s, 1H), 7.52-7.46 (m, 3H), 6.98 (s, 2H), 2.08 (s, 3H). MS (ESI) m/e 253 (M+H)+; m/e 251 (M−H)−.
Reaction SMILES: [CH3:1][Si:2]([CH3:10])([CH3:9])[O:3][C:4]([CH3:8])([C:6]#[CH:7])[CH3:5].[CH3:11][C:12]1([CH3:19])[C:16]([CH3:18])([CH3:17])[O:15][BH:14][O:13]1.C12BC(CCC1)CCC2>O1CCCC1>[CH3:1][Si:2]([CH3:10])([CH3:9])[O:3][C:4]([CH3:8])(/[CH:6]=[CH:7]/[B:14]1[O:15][C:16]([CH3:18])([CH3:17])[C:12]([CH3:19])([CH3:11])[O:13]1)[CH3:5]
Reactant: C#CC(C)(C)O[Si](C)(C)C
Reactant: CC1(C)OBOC1(C)C
Agent: B1C2CCCC1CCC2
Solvent: C1CCOC1
Product: CC(C)(/C=C/B1OC(C)(C)C(C)(C)O1)O[Si](C)(C)C
Temperature: 60 °C
Yield: 22 %

Procedure:
To a solution of trimethyl(2-methylbut-3-yn-2-yloxy)silane (1.5 g, 9.60 mmol) in tetrahydrofuran (15 mL) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.79 mL, 19.19 mmol), followed by addition of 9-BBN (9-borabicyclo[3.3.1]nonane) dimer (0.117 g, 0.480 mmol). This mixture was heated at 60° C. for 24 hours. The reaction was cooled and quenched carefully with saturated ammonium chloride solution. The reaction mixture was extracted with ethyl acetate (2×15 mL). The organics were combined, dried, concentrated and the residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-60% ethyl acetate in hexanes) to afford the title compound (600 mg, 22% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.06-0.08 (m, 9H) 1.19 (s, 12H) 1.25 (s, 6H) 5.41 (d, J=17.85 Hz, 1H) 6.53 (d, J=17.85 Hz, 1H); MS (DCI/NH3) m/z 285 (M+H)+.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:22][C:23]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:24]=1[C:25](Cl)=O.CCOCC>ClCCl>[F:22][C:23]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:24]=1[C:25]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=1
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: O=C(Cl)c1ccc(F)cc1F
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1ccc(-c2nc3ccccc3n2-c2ccccc2)c(F)c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 59.7 %

Procedure:
N-phenyl-1,2-phenylenediamine (1.84 g, 10 mmol) and 40 ml of dichloromethane were charged in a 250 ml round bottle, 3 ml of triethylamine was added, and the mixture was cooled to 0° C. 2,4-Difluoro-benzoyl chloride (1.94 g, 11 mmol) was dissolved in 40 ml of dichloromethane and then slowly added to the 250 ml round bottle. The reaction was conducted under a nitrogen atmosphere for 6 hours. After the reaction was complete, ether was added to form precipitate. The solid product was collected by filtration, washed with ether several times, and heated under reduced pressure to form 2-(2,4-difluoro-phenyl)-1-phenyl-1H-benzoimidazole (yield=1.83 g, 60%).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:5][CH:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]1.[Na+].[I-].[Si]([C:17](F)([F:19])[F:18])(C)(C)C>C1COCC1>[F:18][C:17]1([F:19])[C:2]2([CH2:5][CH:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]2)[CH2:1]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: C=C1CC(C(=O)OCC)C1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1CC2(C1)CC2(F)F
Yield: 73.7 %

Procedure:
The solution of ethyl 3-methylenecyclobutanecarboxylate (1 g, 7.13 mmol), NaI (0.214 g, 1.427 mmol) and TMSCF3 (2.54 g, 17.83 mmol) in THF (10 mL) was stirred at 65° C. for 2 h. The reaction mixture was quenched with a 10% aq. solution of NaHCO3 and the aqueous layer was extracted with diethyl ether (3×10 mL). The combined organic layer was washed with a 10% aq. solution of NaHCO3, followed by brine, then dried over Na2SO4, filtered and the filtrate concentrated. The crude was purified by silica gel chromatography (12 g REDISEP® column, eluting with 20% EtOAc in hexane). Fractions containing the product were combined and evaporated to afford Intermediate 320A as a pale yellow liquid (1 g, 73%, mixture of cis and trans isomers). 1H NMR (400 MHz, chloroform-d) δ ppm 4.13-4.24 (m, 2H) 2.56-2.65 (m, 1H), 2.01-2.06 (m, 2H), 1.91-1.98 (m, 2H) 1.16-1.45 (m, 5H).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10]([CH2:12][OH:13])[N:9]=[C:8]2[S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N+]1([O-])CCOCC1>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:1]1([N:7]2[CH:11]=[C:10]([CH:12]=[O:13])[N:9]=[C:8]2[S:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1cn(-c2ccccc2)c(Sc2ccccc2)n1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: O=Cc1cn(-c2ccccc2)c(Sc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.4 %

Procedure:
To a solution of [1-phenyl-2-(phenylthio)-1H-imidazol-4-yl]methanol (740 mg) in acetonitrile (50 mL) were added tetra-n-propylammonium perruthenate (185 mg), N-methylmorpholine N-oxide (1.42 g) and molecular sieves 4 A powder (5 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=3:2) to give the title compound as a pale-yellow oil (yield 400 mg, 54%).
Reaction SMILES: [C:1]([CH2:9][CH2:10][C:11](O)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[C:2]1([CH:1]([OH:8])[CH2:9][CH2:10][CH2:11][OH:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCC(=O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCCC(O)c1ccccc1
Yield: 80 %

Procedure:
3-Benzoylpropionic acid 11a dissolved in THF was reacted with LiAlH4 according to the general procedure. The following workup procedure was used: H2O was added and THF was evaporated. Diethylether and HCl (2M) was added. The aqueous layer was extracted with diethylether and the combined organic layers were washed with H2O, aqueous NaHCO3 (saturated) and H2O. Drying (MgSO4), filtration and evaporation gave 80% yield of 6a. 1H-NMR: 7.35-7.22 (m, 5H, Ar--H); 4.70 (t, 1H, CH--OH); 3.64 (t, 2H, CH2OH); 3.10 (brs, 1H, CH--OH); 2.60 (brs, 1H, CH2 --OH); 1.84 (q, 2H, CH2 --CHOH); 1.72-1.61 (m, 2H, CH2CH2OH).
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][CH:8](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].[Br:32][CH2:33][CH2:34][CH2:35][CH2:36]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:32][CH2:33][CH2:34][CH2:35][CH2:36][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1/[CH:22]=[CH:21]/[CH:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:31][CH:30]=1)[CH2:9][CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1
Reactant: BrCCCCBr
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2O)Cc2ccc(C#N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCCBr)Cc2ccc(C#N)cc2)cc1

Procedure:
A solution of 664 mg (1.62 mmol) of methyl E-4-[3-(4-cyanobenzyl)-5-(2-hydroxyphenyl)pent-4-enyl]benzoate (enantiomer 1, Example 51A) in 28 ml of dry acetonitrile is mixed with 1743 mg (8.07 mmol) of 1,4-dibromobutane and 446 mg (3.23 mmol) of anhydrous potassium carbonate and then heated under reflux for 12 h. The mixture is subsequently filtered, and the filtrate is evaporated to dryness. The residue is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1). 790 mg (1.44 mmol, 89% of theory) of a colourless oil are isolated.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][C@H:8]2[CH2:12][O:11][C:10](=[O:13])[NH:9]2)=[CH:5][CH:4]=1.Cl.[N:17]([O-])=O.[Na+].[Sn](Cl)[Cl:22]>O>[ClH:22].[NH:2]([C:3]1[CH:15]=[CH:14][C:6]([CH2:7][C@H:8]2[CH2:12][O:11][C:10](=[O:13])[NH:9]2)=[CH:5][CH:4]=1)[NH2:17]
Reactant: Cl[Sn]Cl
Reactant: O=N[O-]
Reactant: Nc1ccc(C[C@H]2COC(=O)N2)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(C[C@H]2COC(=O)N2)cc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 114 %

Procedure:
The product from step (d) (0.79 g) was suspended in water (4.8 ml) and c.HCl (8.1 ml) added dropwise. The resulting mixture was cooled to -5° C. and a solution of sodium nitrite (0.24 g) in water (2.4 ml) added dropwise to the stirred mixture over 15 minutes followed by 30 minutes' stirring at -5° to 0° C. The solution was then added at 0° C. over 15 minutes to a stirred solution of tin (II) chloride (3.8 g) in c.HCl (6.9 ml), followed by 3 hours' stirring at room temperature. The solution was evaporated in vacuo and the residue triturated with ether to give the desired product as a pale yellow solid (0.96 g).
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])=[CH:3][CH:2]=1.[Br:19]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:18][C:1]1[CH:2]=[CH:3][C:4]([N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])=[CH:5][CH:6]=1.[Br-:19]
Reactant: Cc1ccc(N2C(=O)c3ccccc3C2=O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1c1ccc(CBr)cc1
Product: [Br-]
Yield: 121.8 %

Procedure:
To a mixture of 2-p-tolylisoindol-1,3-dione (A) (4.0 g, 17 mmol) and N-bromosuccinimide (3.0 g, 17 mmol) there were added carbon tetrachloride (70 mL) and benzoyl peroxide (8 mL) and the mixture was heated to the boil under halogen radiation over a period of 2 h. The resulting reaction solution was concentrated. The residue was stirred with chloroform (300 mL) with heating for 15 min and the mixture then filtered hot for isolation of the resulting solid matter. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography (SiO2 (150 g) using cyclohexane/EtOAc 4:1 (2000 mL) as eluent). The bromide 2-(4-bromomethylphenyl)isoindol-1,3-dione (B) (4.1 g, 77%) was isolated as a white solid having a melting point of 191-199° C.