Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[CH3:13]C([O-])(C)C.[K+].CI>CN(C=O)C.Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:13])[C:7](=[O:12])[CH2:6][CH2:5]2
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCc2cc(Br)ccc2N1
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a solution of 6-bromo-3,4-dihydro-1H-quinolin-2-one (339 mg, 1.50 mmol) in 15 ml dry DMF was added potassium tert-butylate (336 mg, 3.0 mmol). After the mixture was stirred for 30 min at room temperature, a solution of methyl iodide (426 mg, 3.0 mmol) in 5 ml dry DMF was added. Following overnight stirring, the mixture was diluted with 100 ml 1 N HCl. Extraction with ethyl acetate (2×100 mL) followed by washing of the organic extracts with water and brine, drying over MgSO4 and removal of the solvent in vacuo gave a light yellow solid. Purification by flash chromatography (hexanes/ethyl acetate, 7/3, Rf=0.21) gave 6-bromo-1-methyl-3,4-dihydro-1H-quinolin-2-one (281 mg, 1.17 mmol, 78%) as colorless needles.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][Si](C)(C)C)[C:3]=1[CH2:14][C:15]([O:17]CC)=[O:16]>[OH-].[Na+].CO>[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[CH2:14][C:15]([OH:17])=[O:16])#[CH:9]
Reactant: CCOC(=O)Cc1c(F)cccc1C#C[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1cccc(F)c1CC(=O)O
Temperature: 25 °C
Yield: 103 %

Procedure:
A stirred solution of 331 (607 mg, 2.18 mmol) and IN NaOH (5.5 mL) in methanol (15 mL) was heated at 45° C. for 16 h under nitrogen. The reaction mixture was allowed to cool to room temperature; it was then concentrated, diluted with water, and washed with hexanes. The aqueous layer was collected, acidified with 3N HCl and extracted twice with AcOEt. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated to afford title compound 332 (400 mg, 94% yield, mono-hydrate) as an orange sticky solid. LCMS: 201.1 (M+Na)+.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[H-].[Na+].Cl[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21].O>CN(C)C=O>[OH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][N:6]1[C:5]2[CH:9]=[C:10]([CH3:11])[C:2]([CH3:1])=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: OCCCCCCCl
Reactant: Cc1cc2nc[nH]c2cc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2ncn(CCCCCCO)c2cc1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1.46 g of 5,6-dimethylbenzimidazole dissolved in 50 ml of dry N,N-dimethylformamide was added 0.84 g of NaH, and further, 8.2 ml of 6-chloro-1-hexanol. After the reaction was carried out by stirring the mixture at room temperature for one day, the reaction was stopped by an addition of water. Subsequently, according to the same processes as in Example 1, crude 1-(6-hydroxyhexyl)-5,6-dimethylbenzimidazole was obtained. The conversion to this compound from 5,6-dimethylbenzimidazole was found to be 95% or higher.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[C:36]([C:39]([O:41][CH3:42])=[O:40])[S:37][CH:38]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[CH3:17][O:16][C:12]1[C:11]2[C:7]([C:34]3[CH:35]=[C:36]([C:39]([O:41][CH3:42])=[O:40])[S:37][CH:38]=3)=[N:8][N:9]([CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:10]=2[CH:15]=[CH:14][N:13]=1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cs1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2C1CCOCC1
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: COCCOC
Solvent: O
Product: COC(=O)c1cc(-c2nn(C3CCOCC3)c3ccnc(OC)c23)cs1
Yield: 68.2 %

Procedure:
A solution of 4-methoxy-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (250 mg) obtained in Step A of Example 15, methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (264 mg), tetrakis(triphenylphosphine)palladium(0) (76.0 mg) and 2M aqueous sodium carbonate solution (1.60 mL) in DME (15 mL) was heated overnight with reflux under nitrogen atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (167 mg).
Reaction SMILES: C1(CBr)CC1.Br[CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[CH3:14][C:15]1[N:16]=[C:17]([N:25]2[CH2:29][CH2:28][NH:27][C:26]2=[O:30])[S:18][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH:8]1([CH2:7][N:27]2[CH2:28][CH2:29][N:25]([C:17]3[S:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:15]([CH3:14])[N:16]=3)[C:26]2=[O:30])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: BrCC1CCCCC1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Agent: BrCC1CC1
Product: CCOC(=O)c1sc(N2CCN(CC3CCCCC3)C2=O)nc1C
Yield: 76 %

Procedure:
Following the procedure as described in Example 10, making variations as required to replace cyclopropylmethyl bromide with (bromomethyl)cyclohexane to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 76% yield: 1H NMR (300 MHZ, CDCl3) δ 4.27 (q, J=7.2 Hz, 2H), 4.09-3.99 (m, 2H), 3.57-3.40 (m, 2H), 3.11 (d, J=6.9 Hz, 2H), 2.59 (s, 3H), 1.86-1.55 (m, 5H), 1.31-1.11 (m, 7H), 0.97-0.82 (m, 2H); MS (ES+) m/z 352.3 (M+1).
Reaction SMILES: O[C:2]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([CH3:12])[CH2:4][CH2:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:12][CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:3][CH2:4]1
Reactant: CCOC(=O)C1(O)CCC(C)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1=CCC(C)c2ccccc21
Yield: 93 %

Procedure:
The compound from Example 27 (42 g, 0.18 mole) and p-toluenesulfonic acid (6 g) were dissolved in 500 mL toluene and heated at reflux for 30 minutes with removal of water (Dean-Stark trap). The solution was cooled and washed with saturated sodium bicarbonate, dried over sodium sulfate, filtered and evaporated. The residual syrup was chromatographed on silica gel (0-3% ethyl acetate in heptane) to give the title compound in 93% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[F:36][C:37]1[CH:38]=[N:39][C:40]([O:52][C:53]2[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=2)=[C:41]([CH:51]=1)[C:42]([NH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)=[O:43].CN1CCOCC1>CN(C)C=O>[F:36][C:37]1[CH:38]=[N:39][C:40]([O:52][C:53]2[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=2)=[C:41]([CH:51]=1)[C:42]([NH:44][CH:45]1[CH2:46][CH2:47][N:48]([C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=2[OH:11])[CH2:49][CH2:50]1)=[O:43]
Reactant: Cc1ccc(C(=O)O)c(O)c1
Reactant: O=C(NC1CCNCC1)c1cc(F)cnc1Oc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(=O)N2CCC(NC(=O)c3cc(F)cnc3Oc3ccc(F)cc3)CC2)c(O)c1
Yield: 66.8 %

Procedure:
4-Methylsalicylic acid (91 mg, 0.595 mmol), 1-hydroxybenzotriazole hydrate (110 mg, 0.811 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (135 mg, 0.703 mmol), 5-fluoro-2-(4-fluoro-phenoxy)-N-piperidin-4-yl-nicotinamide hydrochloride (200 mg, 0.541 mmol) (see Preparation 29) and N-methyl morpholine (0.12 ml, 1.08 mmol) were stirred in N,N-dimethylformamide (4 ml) under an atmosphere of nitrogen at room temperature for 18 hours. The reaction mixture was then partitioned between ethyl acetate (10 ml) and water (10 ml), the organic layer separated, washed with a saturated aqueous solution of sodium chloride (10 ml) and dried over anhydrous magnesium sulphate. The solvent was then removed in vacuo and the residue purified via flash column chromatography on silica gel eluting with a solvent gradient of 100% dichloromethane changing to 99:1, by volume, dichloromethane:methanol. The resulting white foam was triturated with pentane (5 ml) giving 5-fluoro-2-(4-fluoro-phenoxy)-N-[1-(2-hydroxy-4-methyl-benzoyl)-piperidin-4-yl]-nicotinamide (169 mg) as a white solid.
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]=2[N:6]=1.[F:15][B-](F)(F)F.[H+].F[B-](F)(F)F.N#[O+]>C(OCC)C>[F:15][C:2]1[S:3][C:4]2[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]=2[N:6]=1
Reactant: CCOC(=O)C1CCc2sc(N)nc21
Reactant: F[B-](F)(F)F
Agent: N#[O+]
Agent: [H+]
Solvent: CCOCC
Product: CCOC(=O)C1CCc2sc(F)nc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 19.3 %

Procedure:
Ethyl 2-amino-5,6-dihydro-4H-cyclopenta[d][1,3]thiazole-4-carboxylate (2.0 g, 9.4 mmol), (see i-13, step A) was dissolved in fluoroboric acid (5.17 g, 28.3 mmol) and the mixture cooled to the point just above it freezes (˜5° C.). Nitrosonium tetrafluoroborate (1.1 g, 9.4 mmol) was added portionwise and mixture stirred at 0° C. for 20min. Diethyl ether (60 ml) added and mixture stirred at −50° C. for 30 min. Filtered and the solid washed with diethyl ether and air dried. The solid was taken up in toluene (70 ml) and warmed to 90° C. for 30 min. The mixture was cooled and evaporated, and the crude residue purified by MPLC (eluent: gradient rising from 100% Hexanes to 40% EtOAc in Hexanes) to give the title compound 390mg (19%) as a yellow oil. 1H NMR (500 MHz CDCl3) δ; 4.22 (q, J=7.1, 2H), 3.93 (dd, J=7.0 and 5.0, 1H), 3.08 (m, 1H), 2.91 (m, 1H), 2.71 (m, 2H), 1.31 (t, J=7.1, 3H).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[C:16]([C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][NH:19]2)=O)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH2:16][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][NH:19]2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(c1c(-c2ccccc2)[nH]c2ccccc12)[C@H]1CCCCN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(-c2[nH]c3ccccc3c2C[C@H]2CCCCN2)cc1
Reaction time: 0.17 h
Yield: 51.9 %

Procedure:
To a suspension of 2.4 g (7.9 mmol) of (2-phenyl-1H-indol-3-yl)piperidin-2(R)-ylmethanone in anhydrous tetrahydrofuran (15 ml) under an atmosphere of nitrogen was added cautiously over 5 min a solution of lithium aluminium hydride (12.5 ml of a 1M solution in tetrahydrofuran, 12.5 mmol) at 0° C. The mixture was heated under reflux for 13 hr, after which it was cooled and quenched by careful addition of water (0.5 ml), 4N NaOH (0.5 ml), and water (1.5 ml). The mixture was stirred for 10 min then filtered through hyflo and evaporated in vacuo to afford 1.2 g (4.1 mmol; 52%) of 2-phenyl-3-(piperidin-2(R)-ylmethyl)-1H-indole as a yellow oil. δH (360 MHz; CDCl3) 1.09-1.26 (1H, m, aliphatic), 1.38-1.52 (1H, m, aliphatic), 1.60-1.74 (3H, m, aliphatics), 1.74-1.90 (1H, m, aliphatic), 2.67-2.80 (1H, m, aliphatic), 3.12-3.25 (1H, m, aliphatic), 3.28-3.38 (2H, m, aliphatics), 3.69 (1H, dd, J 13.8 and 4.2, indole CHAHB), 7.06-7.21 (2H, m, aromatics), 7.29-7.49 (4H, m, aromatics), 7.58 (1H, d, J 7.2, aromatics), 7.81 (1H, d, J 7.6, aromatic), 9.15 (1H, br s, NH); m/z (ES+) 291 (M++H, 100%).
Reaction SMILES: [H-].[Na+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:11]([F:18])([F:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>CS(C)=O>[F:17][C:11]([F:18])([S:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: Sc1ccccc1
Reactant: CCOC(=O)C(F)(F)Br
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)Sc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
60% NaH (0.233 g, 5.81 mmol) was added to a cold (0° C.) solution of thiophenol (0.566 mL, 5.54 mmol) in DMSO (6 mL) and the reaction mixture was allowed to warm to rt over 30 min. Then neat ethyl 2-bromo-2,2-difluoroacetate (1.236 g, 6.09 mmol) was added and the mixture was stirred at rt overnight. The reaction was quenched with satd. NH4Cl and extracted with ether, washed with water, brine and dried (MgSO4). The crude isolate was purified by silica gel FCC (1:1 DCM-hexanes) to afford ethyl 2,2-difluoro-2-(phenylthio)acetate as a clear oil (1.076 g, 84%): 1H NMR (500 MHz, CHLOROFORM-d) δ 7.67-7.62 (m, 2H), 7.52-7.46 (m, 1H), 7.45-7.39 (m, 2H), 4.27 (q, J=7.2 Hz, 2H), 1.28 (t, J=7.2 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH3:17])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:7]=1[C:8]#[N:9].[C:18](Cl)(=[O:20])[CH3:19]>>[C:18]([O:1][CH2:2][CH:3]([CH3:17])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:7]=1[C:8]#[N:9])(=[O:20])[CH3:19]
Reactant: CC(CO)COc1cccc([N+](=O)[O-])c1C#N
Reactant: CC(=O)Cl
Product: CC(=O)OCC(C)COc1cccc([N+](=O)[O-])c1C#N
Yield: 41 %

Procedure:
Prepared as in Example 231c from 2-(3-hydroxy-2-methylpropoxy)-6-nitrobenzonitrile (Example 237d) and acetyl chloride in 41% yield. 1H NMR (400 MHz, DMSO-d6) δ 1.04 (d, J=6.8 Hz, 3H), 2.00 (s, 3H), 2.28-2.33 (m, 1H), 4.05-4.08 (m, 2H), 4.18 (d, J=6.0 Hz, 2H), 7.71-7.73 (m, 1H), 7.86-7.92 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[C:15]1([CH:21]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:22]2[CH2:25][C:24](=[O:26])[CH2:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC1C(C)=C(C)[SiH](C)[SiH-](C)(C)C=1.[Li+]>>[Br:1][C:2]1[CH:3]=[C:4]([C@H:9]([C:24]2([OH:26])[CH2:25][N:22]([CH:21]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:23]2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(=O)Cc1cc(F)cc(Br)c1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CC1=C[SiH-](C)(C)[SiH](C)C(C)=C1C
Agent: [Li+]
Product: CCOC(=O)[C@H](c1cc(F)cc(Br)c1)C1(O)CN(C(c2ccccc2)c2ccccc2)C1

Procedure:
The title compound was prepared from ethyl 3-bromo-5-fluorophenylacetate and 1-[bis-phenylmethyl]azetidin-3-one (Preparation 2) by the procedure described in Step 2 of Preparation 3 except that lithium hexamethyldisilamide was used instead of butyllithium to form the ketene acetal; Mass Spectrum: m/e=498 (M+1, 79Br), 500 (M+1, 81Br)
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: OB(O)c1ccc(F)cc1
Reactant: C=CC[C@]1(c2ccccc2F)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C=CC[C@]1(c2ccccc2F)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3)cc2)C(=O)O1
Yield: 76.9 %

Procedure:
A mixture of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-fluorophenyl)-1,3-oxazinan-2-one (100 mg, 0.24 mmol) and 4-fluorophenylboronic acid (55 mg, 0.36 mmol), Pd(Ph3P)2Cl2 (20 mg), and aq Cs2CO3 solution (0.5 mL, 2 M) in 1,4-dioxane (10 mL) was stirred and heated to reflux for 2 h. The organic phase was separated, and concentrated to give the crude product, which was purified by preparative TLC to give (R)-6-allyl-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(2-fluorophenyl)-1,3-oxazinan-2-one (80 mg, 80%). 1H NMR (CDCl3): δ=1.49 (m, 3H), 2.13 (m, 1H), 2.32 (m, 1H), 2.50 (m, 1H), 2.69 (m, 2H), 2.89 (m, 1H), 5.00 (m, 2H), 5.75 (m, 2H), 6.91-7.10 (m, 6H), 7.15 (m, 1H), 7.22 (m, 2H), 7.38 (m, 2H), 7.48 (m, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:17])[CH2:13][CH2:14][CH2:15][OH:16].[OH-].[K+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[CH3:11][N:12]([CH3:17])[CH2:13][CH2:14][CH2:15][O:16][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CN(C)CCCO
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [K+]
Product: CN(C)CCCOc1ccc([N+](=O)[O-])cc1
Temperature: 85 °C

Procedure:
A mixture of 4-fluoronitrobenzene (2.82 g), 3-dimethylaminopropanol (2.48 g), powdered potassium hydroxide (1.35 g) and Aliquat® 336 (tricaprylylmethylammonium chloride) was heated at 85° C. for one hour. The cooled crude mixture was purified by chromatography on silica gel (eluent: ethyl acetate/methanol 9:1 mixed with 1% v/v triethylamine). The product with the molecular weight of 224.26 (C11H16N2O3); MS (ESI): 225 ([M+H]+), was obtained in this way.
Reaction SMILES: [C:1](=[N:14][NH2:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.II.C(=O)(O)O.NC(N)=N.C(OO)(=O)C>CN(C)C=O.O>[C:2]1([C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N+:14]=[N-:15])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: CC(=O)OO
Agent: II
Agent: N=C(N)N
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Yield: 60.5 %

Procedure:
To benzophenone hydrazone (19.6 g, 0.1 mole) contained in dimethylformamide (100 ml) together with iodine (4 ml, 1% w/v dichloromethane solution) and guanidine carbonate (75.8 g) was added peracetic acid solution (22.8 ml, 1.27 × 0.1 moles) over 60 minutes followed by a stir time of 60 minutes. The reaction mixture was poured into water (1.5 l) and washed in counter-current batch fashion with dichloromethane (200 ml and 3 × 50 ml) and water (3 × 250 ml). A UV assay at 525 nm on a suitably diluted aliquot corresponded to a yield of 60.5%.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[S:6][CH:7]=[C:8]([C:9]([OH:11])=[O:10])[C:4]=2[CH:3]=1.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1.[OH-].[Na+].O>[C:14]1([S:20]([O:1][C:2]2[CH:13]=[CH:12][C:5]3[S:6][CH:7]=[C:8]([C:9]([OH:11])=[O:10])[C:4]=3[CH:3]=2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(O)c1csc2ccc(O)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1csc2ccc(OS(=O)(=O)c3ccccc3)cc12
Yield: 96.5 %

Procedure:
5-Hydroxybenzo[b]thiophene-3-carboxylic acid (11) (M. Martin-Smith et al. J. Chem. Soc (C), 1899-1905 (1967) 8.63 g (44.4 mmol)) was dissolved in aqueous tetrahydrofuran (water content, 20%; 160 ml) and 1 N sodium hydroxide (44 ml). To the solution were added dropwise 0.56 N sodium hydroxide (87 ml) and benzenesulfonyl chloride (6.2 ml, 48.4 mmol) simultaneously with stirring under ice-cooling while maintaining the pH at 11-12. After the completion of the reaction, the mixture was diluted with water, basified, and washed with toluene. The aqueous layer was made slightly acidic by adding concentrated hydrochloric acid with stirring, and the deposited crystals were filtered, washed with water and dried to provide 14.33g of 5-benzenesulfonyloxybenzo[b]thiophene-3-carboxylic acid (12).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]([S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25]C)[CH:20]=1)(=[O:18])=[O:17])[CH:5]2[CH3:27].C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[F:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]([S:16]([C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1)(=[O:18])=[O:17])[CH:5]2[CH3:27]
Reactant: COc1cccc(S(=O)(=O)N2c3ccccc3-c3ccc(F)cc3C2C)c1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: CC1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1cccc(O)c1
Yield: 77 %

Procedure:
The title compound was prepared from 8-fluoro-5-[(3-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (0.50 g, 1.3 mmol), cyclohexene (2.4 mL, 24 mmol), and 1 M boron tribromide in dichloromethane (7.8 mL, 7.8 mmol) according to the procedure and in the same manner as described in Example 47, Step b. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:4), followed by trituration from hexane, to yield 3-[(8-fluoro-6-methylphenanthridin-5(6H)-yl)sulfonyl]phenol as a homogeneous solid (0.37 g, 71%), m.p. 161° C.;
Reaction SMILES: Br[C:2]1[N:3]([CH2:21][CH:22]2[O:26][CH2:25][CH2:24][O:23]2)[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.C([O-])([O-])=O.[Na+].[Na+].[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[C:37]([CH:44]=[O:45])[CH:36]=1>O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:11]1([C:10]2[C:9]3[C:4](=[CH:5][C:6]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][CH:8]=3)[N:3]([CH2:21][CH:22]3[O:23][CH2:24][CH2:25][O:26]3)[C:2]=2[C:38]2[CH:39]=[CH:40][C:35]([O:34][CH3:33])=[CH:36][C:37]=2[CH:44]=[O:45])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COc1ccc(B(O)O)c(C=O)c1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CC3OCCO3)c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OC)cc3C=O)n(CC3OCCO3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a solution of methyl 2-bromo-3-cyclohexyl-1-(1,3-dioxolan-2-ylmethyl)-1H-indole-6-carboxylate in dioxane (0.1 M) was added Na2CO3 (6 eq, 2 M aqueous solution), 4-methoxy-2-formylphenylboronic acid (2 eq) and bis(triphenylphosphine) palladium(II) dichloride (0.2 eq). The mixture was degassed before being heated at reflux for 30 min. RP-HPLC analysis of the reaction mixture showed starting material persisted. The reaction mixture was allowed to cool and an additional 1 eq of 4-methoxy-2-formylphenylboronic acid and 0.1 eq of bis(triphenylphosphine)palladium(II) dichloride introduced. Heating at reflux was then resumed for a further 30 min. The reaction was allowed to cool to RT and partitioned between water and EtOAc. The aqueous fraction was extracted with EtOAc and the combined organics washed with aqueous HCl (1N), water and brine before being dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (10-20% gradient EtOAc/PE) to afford the title compound as a yellow foam (72%); MS (ES+) m/z 478 (M+H)+
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][S@@](C(C)(C)C)=O)[CH3:10])=[C:5]([CH3:18])[CH:4]=1>C(OCC)(=O)C>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH2:11])[CH3:10])=[C:5]([CH3:18])[CH:4]=1
Reactant: Cc1cc(Br)ccc1[C@H](C)N[S@](=O)C(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1cc(Br)ccc1[C@H](C)N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Hydrochloric acid (4 mol/L in 1,4-dioxane, 46 mL) was added to a solution of (R)-2-methyl-propane-2-sulfinic acid [(S)-1-(4-bromo-2-methyl-phenyl)-ethyl]-amide (crude from Step 2, 8.85 g, ca. 75% pure) in ethyl acetate (80 mL) at room temperature. The solution was stirred at room temperature for 1 h and then concentrated. The residue was taken up in water and the resulting mixture was washed with diethyl ether. The aqueous phase was basified using aqueous 1 M NaOH solution and extracted with dichloromethane. The combined extracts were washed with brine, dried (MgSO4), and concentrated to afford the title compound. Yield: 4.04 g (905 of theory); Mass spectrum (ESI−): m/z=214/216 (Br) [M+H]+.