Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:17])[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[CH2:15][OH:16].[F:18][C:19]([F:33])([F:32])[C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:23]Br>CCCCCC.CN(C)C=O>[F:18][C:19]([F:32])([F:33])[C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:27]=1)[CH2:23][O:16][CH2:15][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH3:17]
Reactant: Cc1ccccc1-c1ccncc1CO
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1ccncc1COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (89.1 mg, 2.04 mmol, 1.1 eq) was washed twice with n-hexane under argon and suspended in 1 ml dimethyl formamide. (4-o-Tolyl-pyridin-3-yl)-methanol (370 mg, 1.86 mmol), dissolved in 4 ml dimethyl formamide, was added dropwise and the mixture was stirred 1 h at room temperature. 3,5-Bis(trifluoromethyl)benzyl bromide (627 mg, 2.04 mmol, 1 eq), dissolved in 2 ml dimethyl formamide, was added and the mixture was stirred 2.5 h at room temperature.
Reaction SMILES: [CH3:1][C:2]1[S:3][C@@H:4]2[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:16](=[O:28])[N:5]2[CH:6]([C:8]([O:10]CC(Cl)(Cl)Cl)=[O:9])[CH:7]=1>CN(C)C=O.C(O)(=O)C.[Zn]>[CH3:1][C:2]1[S:3][C@@H:4]2[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:16](=[O:28])[N:5]2[CH:6]([C:8]([OH:10])=[O:9])[CH:7]=1
Reactant: CC1=CC(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC1=CC(C(=O)O)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1
Reaction time: 1.5 h
Yield: 62.8 %

Procedure:
Zinc powder (1.8 g) was added under ice-cooling to a solution of 2,2,2-trichloroethyl 2-methyl-7-(2-phenylacetamido)-2-cephem-4-carboxylate (1.0 g) in a mixture of dimethylformamide (7.5 ml) and acetic acid (2.5 ml), and the mixture was stirred for 1.5 hours, followed by filtration of the reaction mixture, and the filtered zinc was washed with dimethylformamide (2 ml). The filtrate and the washings were combined and the combined solution was poured into a mixture of ethyl acetate (30 ml), ice-water (30 ml) and 10% hydrochloric acid (2 ml), after which the ethyl acetate layer was separated. The aqueous layer was further extracted with ethyl acetate (10 ml). The ethyl acetate layer was combined, and the combined solution was in turn washed with water, a saturated sodium chloride aqueous solution, dried over magnesium sulfate, after which the solvent was distilled off. The residue was crystallized by adding a small quantity of ether, after which the precipitated crystals were collected by filtration and dried to give colorless crystals of 2-methyl-7-(2-phenylacetamido)-2-cephem-4-carboxylic acid (0.45 g), mp 204° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:18]=[C:17]([OH:19])[C:16]([OH:20])=[CH:15][C:4]=2[S:5][C:6]=1[C:7]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:8].[N+:21]([O-])([O-:23])=[O:22].[K+]>CS(O)(=O)=O>[Cl:1][C:2]1[C:3]2[C:18]([N+:21]([O-:23])=[O:22])=[C:17]([OH:19])[C:16]([OH:20])=[CH:15][C:4]=2[S:5][C:6]=1[C:7]([N:9]1[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1)=[O:8]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(c1sc2cc(O)c(O)cc2c1Cl)N1CCOCC1
Agent: CS(=O)(=O)O
Agent: [K+]
Product: O=C(c1sc2cc(O)c(O)c([N+](=O)[O-])c2c1Cl)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(3-Chloro-5,6-dihydroxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-methanone (2.0 g) from Example 28 was slurried in methanesulfonic acid (40 ml) and then potassium nitrate (0.64 g) was gradually added. The reaction mixture was stirred at room temperature and after 15 min it was poured into ice water (100 ml). The solid was filtered, washed with water (50 ml) and dried in vacuum. The resultant solid was dissolved in DMF (6.2 ml) and then ethanol (18.4 ml) was added. The product was filtered and washed with methanol (15 ml).
Reaction SMILES: CS[C:3]1[N:4]([CH2:8][C:9]2([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:17][CH:16]=3)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][N:7]=1>CCO.O.[Ni]>[N:25]1([CH2:24][CH2:23][CH2:22][O:21][C:18]2[CH:19]=[CH:20][C:15]([C:9]3([CH2:8][N:4]4[CH:5]=[CH:6][N:7]=[CH:3]4)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:16][CH:17]=2)[CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CSc1nccn1CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: c1cn(CC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)cn1
Yield: 35.5 %

Procedure:
To a solution of 2-(methylthio)-1-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)-1H-imidazole (90 mg, 0.22 mmol) in EtOH (4 ml) and water (1 ml) was added Raney Nickel (50% slurry in water) in 200 mg aliquots every 30 min. After 3 h all starting material had been consumed. The mixture was filtered through Arbocel® with EtOH (200 ml) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (90:10:1) to provide the title compound as a yellow oil (29 mg, 0.078 mmol, 36%). 1H NMR (400 MHz, CDCl3) δ 1.80-2.00 (m, 6H), 2.10 (m, 4H), 2.70-2.90 (m, 6H), 3.50 (t, 2H), 3.81 (m, 2H), 3.97 (s, 2H), 4.04 (t, 2H), 6.32 (s, 1H), 6.80-6.90 (m, 4H), 6.98 (d, 2H). HRMS ESI+ m/z 370.2485 [MH]+.
Reaction SMILES: Cl[C:2]1[C:10]2[C:9]3[CH:11]=[C:12]([C:15]#[N:16])[N:13]=[CH:14][C:8]=3[N:7]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=2[N:5]=[CH:4][CH:3]=1.[OH:25][C@H:26]1[CH2:30][CH2:29][N:28](O)[CH2:27]1>CN(C)C(=O)C.C(OCC)(=O)C>[OH:25][C@H:26]1[CH2:30][CH2:29][N:28]([C:2]2[C:10]3[C:9]4[CH:11]=[C:12]([C:15]#[N:16])[N:13]=[CH:14][C:8]=4[N:7]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=3[N:5]=[CH:4][CH:3]=2)[CH2:27]1
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(Cl)ccnc21
Reactant: O[C@H]1CCN(O)C1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(N3CC[C@H](O)C3)ccnc21
Temperature: 100 °C

Procedure:
A mixture of 4-chloro-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (130 mg, 0.36 mmol) and (S)-3-hydroxypyrrolidinol (91 mg, 1.04 mmol) in N,N-dimethylacetamide (1.6 mL) was heated at 100° C. for 2 hours. The cooled reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (silica, 4 g, ISCO, 0-100% ethyl acetate in heptane) to afford the title compound as a white waxy solid, which was used in the next step without further purification (140 mg, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N+:37]([O-:39])=[O:38])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].CCCCCC>C1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:30]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N+:37]([O-:39])=[O:38])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CCCCCCCCCCCCCCCCNc1ccccc1[N+](=O)[O-]
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: c1ccccc1
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCCN(C(=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccccc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
A solution of 33 g of 4-chloro-3-nitro-benzoyl chloride in 100 ml of benzene is added dropwise in the course of one hour to a solution, which has been heated to the reflux temperature, of 54.3 g of N-n-hexadecyl-2-nitroaniline in 80 ml of benzene. After a further two hours, the reaction has ended. The reaction solution is poured into 600 ml of hexane and the mixture is left to stand overnight. The resulting crystals are filtered off with suction and washed with hexane. This gives 48 g of the compound with a melting point of 83° to 85° C.
Reaction SMILES: [CH2:1]([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)=[CH:9][C:8]=1[C:22]([F:25])([F:24])[F:23]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[CH2:1])=[CH:16][CH:15]=2)=[CH:9][C:8]=1[C:22]([F:25])([F:24])[F:23]
Reactant: O=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
An alternative synthesis was provided to prepare the compound of D21: To a suspension of methyltriphenylphosphonium bromide (64.7 g, 181 mmol) in anhydrous tetrahydrofuran (THF) (20 mL) was added dropwise n-butyllithium (113 mL, 181 mmol) under −78° C. over 30 mins. The reaction mixture was stirred for 1 h, and then was added a solution of 4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}benzaldehyde (36.3 g, 121 mmol) in anhydrous tetrahydrofuran (15 ml). The reaction mixture was warmed slowly to room temperature and stirred overnight at room temperature. The mixture was quenched with water and extracted with ethyl acetate. The organic phase was dried with anhydrous Na2SO4 and concentrated under reduced pressure. The crude sample was purified by silica gel column (220 g) using hexane/ethyl acetate (20:1) as eluent to afford the title compound (28 g, 94 mmol, 78% yield) LCMS: rt=4.29 min.
Reaction SMILES: C(O[CH2:5][CH:6]=[CH2:7])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:27]([C:30]1[C:31](=[O:40])[NH:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=1)([O-:29])=[O:28]>C1COCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N+:27]([C:30]1[C:31](=[O:40])[N:32]([CH2:7][CH:6]=[CH2:5])[C:33]([C:36]([F:39])([F:37])[F:38])=[CH:34][CH:35]=1)([O-:29])=[O:28]
Reactant: O=c1[nH]c(C(F)(F)F)ccc1[N+](=O)[O-]
Reactant: C=CCOC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCn1c(C(F)(F)F)ccc([N+](=O)[O-])c1=O
Reaction time: 24 h
Yield: 33.8 %

Procedure:
A solution of allyl acetate (13.5 ml, 125 mmol) in THF (8 ml), was evacuated and purged with argon (3 times). Palladium acetate (122 mg, 0.50 mmol) and triphenylphosphine (525 mg, 2.0 mmol) were added as solutions in tetrahydrofuran (1.5 ml each), followed by 3-nitro-6-trifluoromethyl-2-pyridinone (2.6 g, 12.5 mmol) in THF (2 ml). The reaction was heated to reflux for 64 h, and more allyl acetate (13.5 ml, 125 mmol), triphenylphosphine (525 mg, 2.0 mmol), palladium acetate (122 mg, 0.5 mmol), and tetrahydrofuran (13 ml) were added. After a further 24 h and 48 h at reflux addditional allyl acetate (13.5 ml, 125 mmol), palladium acetate (122 mg, 0.5 mmol), and triphenylphosphine (525 mg, 2.0 mmol) were added and the reaction was heated to reflux for a further 24 h. The reaction was cooled and evaporated in vacuo to a gum which was purified by flash column chromatography on silica (15% ethyl acetate/hexane) to give the product contaminated with unreacted 3-nitro-6-trifluoromethyl-2-pyridinone. This material was diluted with ethyl acetate and washed with water adjusted to pH 12 with sodium carbonate, dried (Na2SO4), and evaporated in vacuo to give the title compound (1.05 g): 1H NMR (CDCl3) selected signals at δ 4.80 (d, J=5.8 Hz, 2H), 5.28-5.33 (m, 2H), 5.86-5.96 (m, 1H), 6.80 (d, J=7.9 Hz, 1H), 8.22 (d, J=7.9 Hz, 1H).
Reaction SMILES: C([O:5][C:6](=[O:35])[C:7]([CH3:34])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[N:14]=1)[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:34][C:7]([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[N:14]=1)([CH3:8])[C:6]([OH:35])=[O:5]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(COCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(Sc1nc(COCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.3 %

Procedure:
2-Methyl-2-{[4-({[4′-(trifluoromethyl)biphenyl-4-yl]methoxy}methyl)-1,3-thiazol-2-yl]thio}propionic acid tert-butyl ester (900 mg) obtained in Example 152-2 was dissolved in dichloromethane (10 mL), trifluoroacetic acid (4 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 0:1) to give the title compound (420 mg) as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)=[O:8].[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C(O)C>[OH:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:26]2[CH2:27][CH2:28][N:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:24][CH2:25]2)=[CH:11][CH:12]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(CCCCCBr)Nc1ccc(O)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(CCCCCN1CCN(c2ccccc2)CC1)Nc1ccc(O)cc1

Procedure:
A solution of 45.7 g (0.16 mol) of 6-bromo-N-(4-hydroxyphenyl)hexanamide, 26.0 g (0.16 mol) of 1-phenylpiperazine and 22.4 ml (16.3 g, 0.16 mol) of triethylamine in 400 ml of ethanol was heated under reflux overnight and then concentrated under vacuum. The residue was mixed with sodium bicarbonate solution and trichloromethane. The resulting suspension was filtered. The solid was recrystallized from ethanol-water and then from acetonitrile to give the end product as tan crystals, mp 157°-159°.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])O[C:2]2=O.[CH2:13](Br)CCCCC>>[NH:6]1[C:7]2[C:1](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:2]=[CH:13][C:5]1=[O:12]
Reactant: CCCCCCBr
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Product: O=c1ccc2ccccc2[nH]1

Procedure:
Following the procedure set forth in Steps (2) to (4) of Preparation A, isatoic anhydride was reacted with hexyl bromide to give 1-hexyl-4-hydroxy-(2(1H)-quinolinone. That the expected product was obtained was confirmed by the spectral data: MS: role 245 (M·+); NMR (DMSO): δ0.9 (t, 3H, CH3 --CH2 --), 4.06 (t, 2H, N--OH2), 6.18 (s, 1H, =CH), 11.87 (br, 1H, OH) ppm.
Reaction SMILES: [C:1]([C:9]1[N:10]([NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])[CH:11]=[CH:12][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](=O)([O-])[O-].[Na+].[Na+].CI>CN(C)C=O>[C:1]([C:9]1[N:10]([N:14]([CH3:20])[C:15](=[O:19])[O:16][CH2:17][CH3:18])[CH:11]=[CH:12][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)Nn1cccc1C(=O)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)N(C)n1cccc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
(2-Benzoyl-1H-pyrrol-1-yl)-carbamic acid, ethyl ester (18.5 g, 71.6 mmol) was combined with sodium carbonate (16.0 g, 157 mmol) and methyl iodide (13.2 g, 93 mmol) in 100 ml of dimethylformamide. The resulting slurry was stirred at ambient temperature for 20 hours and then at 75° C. for 2 hours. This reaction mixture was poured into 300 ml of crushed ice and extracted with four 200 ml portions of ether. The combined extracts were washed with water, dried over MgSO4, filtered and evaporated to an oil which was purified by HPLC (silica gel, 15% hexane/DCM). The resulting material was recrystallized from ether-hexane to give 18.4 g (94%) of cubes, m.p. 50°-52°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH:10]=[CH2:11])[CH:3]=1.Cl[Sn](Cl)(Cl)Cl.[I:17]I>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH:10]([CH2:11][I:17])[CH2:9][C:4]=2[CH:3]=1
Reactant: C=CCc1cc(F)ccc1O
Reactant: II
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: Fc1ccc2c(c1)CC(CI)O2
Reaction time: 18 h
Yield: 54.7 %

Procedure:
To a solution of 4-fluoro-2-(prop-2-en-1-yl)phenol (5 g, 32.9 mmol) in dichloromethane (125 mL) was added SnCl4 (4.28 g, 16.5 mmol) and iodine (8.36 g, 32.9 mmol) at room temperature. After an additional 18 hours, the reaction was quenched with water (150 ml) and the pH value was adjusted to 8 with aqueous NaOH solution (2N). The organic layer was separated and the aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic layer was washed with Na2S2O4 (3×100 mL, 5%) to remove iodine and dried over anhydrous magnesium sulfate. The solution was filtered and then concentrated under vacuum. The crude residue was purified by a silica gel column, eluted with 0.5-1% ethyl acetate in petroleum ether to afford 5-fluoro-2-(iodomethyl)-2,3-dihydro-1-benzofuran as a yellow oil (5 g, 54%); 1H NMR (300 MHz, DMSO): δ 7.03-7.08 (dd, J=5.7 Hz, 8.4 Hz, 1H), 6.93-6.86 (dt, J=2.7 Hz, 8.7 Hz, 1H), 6.76-6.70 (m, 1H), 4.88-4.79 (m, 1H), 3.49-3.60 (m, 2H), 3.41-3.32 (dd, J=7.2 Hz, 16.5 Hz, 1H), 2.96-2.88 (dd, J=7.2 Hz, 16.5 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:31]([O:32][CH3:33])=[CH:30][C:6]2[CH2:7][C:8](=O)[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:28])[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:43]2)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:31]([O:32][CH3:33])=[CH:30][C:6]2[CH2:7][C:8](=[S:43])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:28])[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(CCN(C)CCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC
Solvent: Cc1ccccc1
Product: COc1ccc(CCN(C)CCCN2CCc3cc(OC)c(OC)cc3CC2=S)cc1OC

Procedure:
2.28 gm (0.005 mol) of 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-[N-methyl-N-(2-{3,4-dimethoxy-phenyl}-ethyl)-amino]-propane were dissolved in 10 ml of absolute toluene, and the solution was refluxed for 50 minutes with 1.0 gm (0.0025 mol) of 2,4-bis-(4-methoxy-phenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide. After the solvent had been removed in vacuo in a rotary evaporator, the residue was purified on aluminium oxide with methylene chloride plus 2% ethanol as the eluant.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[CH2:16][N:15]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.O.NN>CO.[Fe](Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[CH2:16][N:15]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: CCCN1CCC=C(c2ccc([N+](=O)[O-])c(C)c2)C1
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: CO
Solvent: O
Product: CCCN1CCC=C(c2ccc(N)c(C)c2)C1
Temperature: 64 °C
Reaction time: 5 h
Yield: 81.4 %

Procedure:
To 5-(3-methyl-4-nitrophenyl)-1-propyl-1,2,3,6-tetrahydropyridine (5.0 g, 19.2 mmol) in MeOH (100 mL) was added iron (III) chloride (0.93 g, 5.8 mmol, Aldrich) and activated carbon (1.0 g, Aldrich). The reaction mixture was stirred at 64° C. for 20 min before the dropwise addition of hydrazine hydrate (11.5 mL, 230.8 mmol, Aldrich) over 5 min. The reaction was kept stirring at 64° C. for additional 5 h. Filtration removed the solids and the filtrate was concentrated and purified via chromatography on SiO2 (0-10% 2 M NH3 in MeOH/DCM) to afford 2-methyl-4-(1-propyl-1,2,5,6-tetrahydro-3-pyridinyl)aniline (3.6 g, 82% yield.) 1H NMR (400 MHz, CDCl3) δ ppm 0.94 (t, J=7.4 Hz, 3 H), 1.57-1.67 (m, 2 H), 2.16 (s, 3 H), 2.33 (tt, J=5.9, 2.9 Hz, 2 H), 2.44-2.50 (m, 2 H), 2.59 (t, J=5.8 Hz, 2 H), 3.29 (q, J=2.0 Hz, 2 H), 3.58 (s, 2 H), 5.96 (dq, J=3.9, 2.0 Hz, 1 H), 6.61 (d, J=7.9 Hz, 1 H), 7.02-7.06 (m, 2 H).
Reaction SMILES: [OH:1][CH:2]([CH3:11])/[CH:3]=[C:4](\[CH3:10])/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:12]([O:14][P:15](Cl)([O:17][CH2:18][CH3:19])=[O:16])[CH3:13]>N1C=CC=CC=1>[CH2:12]([O:14][P:15]([O:17][CH2:18][CH3:19])([O:1][CH:2]([CH3:11])/[CH:3]=[C:4](\[CH3:10])/[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:16])[CH3:13]
Reactant: CCOP(=O)(Cl)OCC
Reactant: CCOC(=O)/C(C)=C/C(C)O
Solvent: c1ccncc1
Product: CCOC(=O)/C(C)=C/C(C)OP(=O)(OCC)OCC
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 88 %

Procedure:
29 (rac-Ethyl (2E)-4-hydroxy-2-methylpent-2-enoate) (0.99 g, 6.0 mmol) is dissolved in pyridine (1.6 ml) and cooled to 0° C. Diethylchlorophosphate (1.1 ml, 7.5 mmol) is added under stirring over 20 min at ≧3° C. After 4.5 hours of additional stirring at 0° C., the reaction mixture is quenched with 1 M H2SO4 (100 ml) and extracted with tBuOMe (300 ml) successively. The organic phase is washed with brine (50 ml), saturated NaHCO3 (50 ml) and brine (50 ml). The organic phase is dried with Na2SO4 and evaporated under reduced pressure at 40° C. The residue is purified by flash chromatography (AcOiPr:heptane fraction 50:50 to 60:40) to yield 17 (rac-Ethyl (2E)-4-(diethoxyphosphinyloxy)-2-methylpent-2-enoate) (1.56 g, 88%) as a yellowish oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([OH:7])[CH2:5][CH3:6].[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>N1C=CC=CC=1>[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:7][CH:4]([CH2:5][CH3:6])[CH2:3][O:2][CH3:1])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(O)COC
Solvent: c1ccncc1
Product: CCC(COC)OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-methoxybutan-2-ol (1.10 mL) in pyridine (5 mL) was added dropwise a solution of 4-methylbenzenesulfonyl chloride (2.75 g) in pyridine (15 mL) over 30 min or more at 0° C. The reaction mixture was stirred overnight at room temperature, and poured into ice-water. The reaction mixture was stirred at 0° C. for 1 hr, and the precipitate was collected by filtration, and washed with cold water. The obtained solid was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.23 g).
Reaction SMILES: [CH3:1][C:2]1[S:11][C:10]2[C:9](=[CH2:12])[C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=1.[CH3:17][S:18]([NH:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)(=[O:20])=[O:19]>>[CH3:1][C:2]1[S:11][C:10]2[C:9](=[CH:12][C:26]3[CH:27]=[C:22]([NH:21][S:18]([CH3:17])(=[O:19])=[O:20])[CH:23]=[CH:24][CH:25]=3)[C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Reactant: C=C1c2ccccc2CCc2nc(C)sc21
Product: Cc1nc2c(s1)C(=Cc1cccc(NS(C)(=O)=O)c1)c1ccccc1CC2

Procedure:
Following procedures essentially as described in Preparation 24 followed by procedures essentially as described in Example 219, and using 2-methyl-4-methylene-9,10-dihydro-4H-3-thia-1-aza-benzo[f]azulene and 3-methanesulfonylaminophenylboronic acid, the title compounds are made.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][C:15]([F:25])([F:24])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29](=[O:47])[CH:30]([C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=1)[CH3:31])[CH3:27]>>[CH2:26]([O:28][C:29](=[O:47])[CH:30]([C:32]1[CH:37]=[CH:36][C:35]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH2:14][C:15]([F:25])([F:24])[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][CH:3]=2)=[CH:34][CH:33]=1)[CH3:31])[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CC(F)(F)CCc1ccccc1
Reactant: CCOC(=O)C(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)C(C)c1ccc(-c2ccc(-c3onc(C)c3CC(F)(F)CCc3ccccc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 5-(4-bromo-phenyl)-4-(2,2-difluoro-4-phenyl-butyl)-3-methyl-isoxazole and 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic acid ethyl ester.