Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.Br[C:22]1[C:23](=[O:30])[N:24]([CH3:29])[CH:25]=[C:26]([Br:28])[CH:27]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[Br:28][C:26]1[CH:27]=[C:22]([NH:1][C:2]2[N:3]=[CH:4][C:5]([N:8]3[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]3)=[N:6][CH:7]=2)[C:23](=[O:30])[N:24]([CH3:29])[CH:25]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc(N)cn2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2cnc(N3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1=O
Temperature: 120 °C
Yield: 49.1 %

Procedure:
A mixture of 189d (1.1 g, 3.94 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (1.1 g, 3.94 mmol), palladium diacetate (45 mg, 0.20 mmol), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (245 mg, 0.39 mmol), and Cs2CO3 (2.6 g, 7.9 mmol) in 1,4-dioxane (150 mL) was heated at 120° C. for 2 hours. It was then cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 30:1 dichloromethane/methanol to afford 189e (900 mg, 54%). MS: [M+H]+ 465.1.
Reaction SMILES: [CH:1]([OH:3])=O.[CH:4]1([O:9][C:10]2[C:15]([O:16][CH3:17])=[CH:14][N:13]=[C:12](OC(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5]1>C(OCC)(=O)C>[CH:4]1([O:9][C:10]2[C:15]([O:16][CH3:17])=[CH:14][N:13]=[C:12]([CH2:1][OH:3])[CH:11]=2)[CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: O=CO
Reactant: COc1cnc(OC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1OC1CCCC1
Solvent: CCOC(C)=O
Product: COc1cnc(CO)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
90% Formic acid (5.5 mL) is added to a suspension of 4-cyclopentyloxy-5-methoxy-2-trityloxypyridine (1.2 g) in ethyl acetate (8.5 mL) and the mixture stirred at room temperature for 1 hours. The mixture is diluted with ethyl acetate and washed with brine then aqueous sodium bicarbonate until the washings are neutral. The brine washings are neutralised with solid sodium bicarbonate and extracted with ethyl acetate. After drying (MgSO4) the extracts are evaporated to give 4-cyclopentyloxy-2-hydroxymethyl-5-methoxypyridine (360 mg) as a white solid, m.p. 93-94.5° C. [Elemental analysis: C, 64.7; H, 7.80; N, 6.11%. calculated: C, 64.55; H, 7.68; N, 6.27%.].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11](=[O:28])[NH:12][CH:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:14]([F:17])([F:16])[F:15])[NH:8]2)=[CH:4][C:3]=1[CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34].[H-].[Na+].I[CH2:41][CH3:42].O>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11](=[O:28])[NH:12][CH:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:27])[F:26])[CH:19]=3)[C:14]([F:16])([F:17])[F:15])[N:8]2[CH2:41][CH3:42])=[CH:4][C:3]=1[CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)NCc1cc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)[nH]c2cc1Cl
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1c(C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc2cc(CNC(=O)OC(C)(C)C)c(Cl)cc21
Yield: 60.1 %

Procedure:
tert-Butyl {[6-chloro-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indol-5-yl]methyl}carbamate (90% pure; 0.74 g, 1.21 mmol) was dissolved under argon at 0° C. in N,N-dimethylformamide (12.5 ml). Sodium hydride (60%; 0.053 g, 1.33 mmol) was added and the mixture was stirred while cooling with ice for 2 h. Subsequently, iodoethane (0.19 g, 1.21 mmol) was added dropwise. The reaction mixture was thawed while stirring within 16 h. Water and ethyl acetate were added and the phases were separated. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulphate, and the solvent was removed under reduced pressure. The residue was chromatographed with cyclohexane/ethyl acetate (4/1) and gave 0.42 g (60% of theory) of tert-butyl {[6-chloro-1-ethyl-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indol-5-yl]methyl}carbamate.
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([CH3:11])[C:6]=2[CH:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:3]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23].[I:24]N1C(=O)CCC1=O.C(O)(C(F)(F)F)=O>CN(C=O)C>[F:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([CH3:11])[C:6]=2[CH:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:3]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:24])=[CH:19][C:18]=1[F:23]
Reactant: COC(=O)c1cc2c(C)noc2c(F)c1Nc1ccccc1F
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(C)noc2c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a suspension of methyl 7-fluoro-6-(2-fluorophenylamino)-3-methylbenzo[d]isoxazole-5-carboxylate (2.84 g, 8.93 mmol) in DMF (50 ml) were added N-iodosuccinimide (3.01 g, 13.4 mmol) and TFA (3 ml). After stirring at room temperature for 4 h, the reaction was quenched with saturated aqueous NH4Cl solution (100 ml) and extracted with EtOAc (2×100 ml). The combined organic solution was washed with brine (100 ml), dried over MgSO4 and concentrated. Silica gel chromatography (EtOAc:Hexanes=25:75) yielded 3.77 g (95%) of methyl 7-fluoro-6-(2-fluoro-4-iodophenylamino)-3-methylbenzo[d]isoxazole-5-carboxylate as a tan solid.
Reaction SMILES: C([O:3][C:4](=[O:22])/[C:5](/[CH3:21])=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:8]=1)C.O[Li].O>CO.O>[CH:16]1([O:15][C:9]2[CH:8]=[C:7](/[CH:6]=[C:5](\[CH3:21])/[C:4]([OH:22])=[O:3])[CH:12]=[CH:11][C:10]=2[O:13][CH3:14])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CCOC(=O)/C(C)=C/c1ccc(OC)c(OC2CCCC2)c1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: COc1ccc(/C=C(\C)C(=O)O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.8 %

Procedure:
A suspension of (E)-3-(3-cyclopentoxy-4-methoxyphenyl)-2-methyl-acrylic acid ethyl ester (30 g, 98.6 mmol) and LiOH·H2O (lithium hydroxide hydrate) (5.0 g, 119.2 mmol, 1.2 equiv.) in methanol-water (4:1, 100 mL) was stirred at room temperature for 24 hours. Methanol was removed under reduced pressure and the resulting residue was dissolved in water (100 mL), washed with three 100 mL portions of ethyl acetate, neutralized with 1.0 N HCl (hydrochloric acid) (100 mL), and extracted with two 150 mL portions of ethyl acetate. The extract was washed with brine, dried over anhydrous Na2SO4 (sodium sulfate), and concentrated under reduced pressure to afford the desired product as a light yellow powder (18.2 g, 66% yield). 1H NMR (300 MHz, CDCl3) δ (ppm): 12.4 (br. s, 1H, COOH), 7.56 (s, 1H, olefinic), 7.04 (m, 3H, aromatic), 4.81 (m, 1H), 3.78 (s, 3H, OCH3), 2.06 (s, 3H, CH3), 1.91-1.57 (m, 8H, cyclopentyl).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])(=[O:3])[CH3:2].[ClH:12].[CH3:13][CH2:14][O:15]CC>C(O)C>[ClH:12].[CH2:14]([O:15][C:7](=[NH:8])[C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=1)[CH3:13]
Reactant: CC(=O)c1cccc(C#N)c1
Reactant: CCOCC
Agent: Cl
Solvent: CCO
Product: CCOC(=N)c1cccc(C(C)=O)c1
Reaction time: 48 h

Procedure:
A solution of 7.25 g (0.05 mol) of 3-acetylbenzonitrile in 150 ml of ether and 4.5 ml of ethanol is saturated at 0° with dry hydrochloric acid gas and then left to stand at 0° for 2 days. The product which crystallises out is filtered off and recrystallised from ethanol/ether; m.p. 110° (with decomposition).
Reaction SMILES: [Si:1]([O:8][CH:9]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH:13]1[F:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:26][S:27]([O:18][CH:15]1[CH2:16][CH2:17][CH:12]([O:11][CH2:10][CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:13]([F:19])[CH2:14]1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OC(COC1CCC(O)CC1F)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OC(COC1CCC(OS(C)(=O)=O)CC1F)c1ccccc1
Reaction time: 0.02 h
Yield: 95.5 %

Procedure:
To a solution of 4-(2-{[tert-Butyl(dimethyl)silyl]oxy}-2-phenylethoxy)-3-fluorocyclohexanol (8.46 g, 22.9 mmol) in dichloromethane (100 mL) at 0° C. was added methanesulfonyl chloride (2.49 mL, 32.1 mmol) and diisopropylethylamine (11.1 mL, 64.1 mmol). The reaction mixture was stirred for 1 min, diluted with dichloromethane and washed with 5% potassium bisulfate. The layers were separated and the aqueous extracted with dichloromethane (3×). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated. Purification by flash column chromatography (hexane: ethyl acetate 70:30) gave 4-(2-{[tert-Butyl(dimethyl)silyl]oxy}-2-phenylethoxy)-3-fluorocyclohexyl methanesulfonate (9.77 g, 100% yield) as a clear oil.
Reaction SMILES: [C:1]1([OH:13])[CH:12]=[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:5]=[C:3]([OH:4])[CH:2]=1.O.[C:15]1(O)([CH3:24])[CH2:20][CH2:19][CH:18]([C:21]([CH3:23])=[CH2:22])[CH:17]=[CH:16]1>ClCCl.[Cl-].[Zn+2].[Cl-]>[CH3:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]1[CH:12]=[C:1]([OH:13])[C:2]([C@@H:17]2[C@@H:18]([C:21]([CH3:23])=[CH2:22])[CH2:19][CH2:20][C:15]([CH3:24])=[CH:16]2)=[C:3]([OH:4])[CH:5]=1
Reactant: CCCCCc1cc(O)cc(O)c1
Reactant: C=C(C)C1C=CC(C)(O)CC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: O
Product: C=C(C)[C@H]1CCC(C)=C[C@@H]1c1c(O)cc(CCCCC)cc1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.4 %

Procedure:
A mixture of olivetol (3.6 g, 20 mmol), zinc chloride (3.5 g, 26 mmol), water (3.5 mL, 19 mmol) and dichloromethane (35 mL) was refluxed for 1 hour. A solution of (−)-p-mentha-2,8-dien-1-ol (3.0 g, 20 mmol) in dichloromethane (10 mL) was added drop-wise over 0.75 hour to the refluxing mixture, and the resultant reaction mixture was mixed for 0.5 hours at reflux. The mixture was cooled to 25° C., ice water (50 mL) was added, and the resultant biphasic mixture stirred for 20 minutes at 0° C. The resultant organic phase was collected, washed with water (2×20 mL) and 5% NaHCO3 (20 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to provide 6.0 g of first crude (+)-CBD residue. Analysis (GC) of the first crude (+)-CBD residue indicated that it contained (+)-CBD (46.9%) and abn-(−)-CBD (19.7%). The first crude (+)-CBD residue was purified by column chromatography on silica gel (eluent MTBE/hexane) to provide 2.4 g of a second crude (+)-CBD residue.
Reaction SMILES: [CH2:1]([O:8][P:9]([OH:19])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:27]([CH2:56][CH3:57])[C:28]([NH:30][C:31]1[NH:35][C:34]2[C:36]([C@H:51]3[CH2:55][CH2:54][CH2:53][O:52]3)=[C:37]([F:50])[C:38]([C:40]3[CH:41]=[N:42][C:43]([C:46](O)([CH3:48])[CH3:47])=[N:44][CH:45]=3)=[CH:39][C:33]=2[N:32]=1)=[O:29])(OC(C)(C)C)=O.O.C(O)(C(F)(F)F)=O.CO>C(Cl)Cl>[P:9]([O:19][C:46]([C:43]1[N:42]=[CH:41][C:40]([C:38]2[C:37]([F:50])=[C:36]([C@H:51]3[CH2:55][CH2:54][CH2:53][O:52]3)[C:34]3[NH:35][C:31]([NH:30][C:28]([NH:27][CH2:56][CH3:57])=[O:29])=[N:32][C:33]=3[CH:39]=2)=[CH:45][N:44]=1)([CH3:47])[CH3:48])([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: O=P(O)(OCc1ccccc1)OCc1ccccc1
Reactant: CCN(C(=O)Nc1nc2cc(-c3cnc(C(C)(C)O)nc3)c(F)c([C@H]3CCCO3)c2[nH]1)C(=O)OC(C)(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNC(=O)Nc1nc2cc(-c3cnc(C(C)(C)OP(=O)(OCc4ccccc4)OCc4ccccc4)nc3)c(F)c([C@H]3CCCO3)c2[nH]1
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a solution of Boc-1-ethyl-3-[6-fluoro-5-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-7-[(2R)-tetrahydrofuran-2-yl]-1H-benzimidazol-2-yl]urea dibenzyl phosphate (26) (11.9 g, 15.09 mmol) in DCM (300 mL) at 23° C. was added water (2.325 mL, 129.1 mmol) then TFA (3.441 g, 2.325 mL, 30.18 mmol). After 1 h, only partial conversion was observed by tlc, so more TFA (3.441 g, 2.325 mL, 30.18 mmol) was added. After a further 2.5 h, MeOH (2 mL) was added and the mixture stirred a further 18 hours. The reaction mixture was washed with 1:1 brine:saturated aqueous sodium bicarbonate (200 mL). The aqueous layer was re-extracted with DCM (150 mL), the organic layers combined, then dried (over magnesium sulfate), filtered and concentrated in vacuo. The resulting residue was re-dissolved in EtOAc (200 mL) washed with water (150 mL) and brine (100 mL), then dried (magnesium sulfate) filtered and concentrated to give (R)-dibenzyl 2-(5-(2-(3-ethylureido)-6-fluoro-7-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)propan-2-yl phosphate (24) (10.21 g, 14.83 mmol, 98.27%) as a white solid. ESMS (M+1)=689.4; 1H NMR (300 MHz, CD3OD) δ 8.88 (d, J=1.6 Hz, 2H), 7.37 (d, J=6 Hz, 1H), 7.30 (m, 10H), 5.38-5.33 (m, 1H), 5.12-5.01 (m, 4H), 4.24 (dd, J=6.8, 14.9 Hz, 1H), 3.98 (dd, J=6.9, 15.1 Hz, 1H), 3.35-3.27 (m, 3H), 2.52 (q, J=5.9 Hz, 1H), 2.14-2.05 (m, 2H), 1.91 (s, 6H) and 1.22-1.14 (m, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1Br.C([Li])CCC.[B:14](OC(C)C)([O:19]C(C)C)[O:15]C(C)C>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:14]([OH:19])[OH:15]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccccc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
A solution of 50 g (285.6 mmol) of 2-fluorobromobenzene in 400 mL of tetrahydrofuran was cooled to −78° C. and 200 mL (320.0 mmol) of 1.6M n-Butyllithium was added via a cannula. The mixture was stirred at −78° C. for 60 minutes, then 98.9 mL (428.4 mmol) of triisopropyl borate was added via a cannula and stirring was continued for 60 minutes. The cooling bath was removed and the mixture was stirred at ambient temperature for 1.5 hours, then 150 mL of 6N hydrochloric acid was added and stirring was continued for 1.5 hours. To the mixture was added 100 mL of brine, and then the organic layer was separated and the aqueous layer was extracted three times with 30 mL each of ether. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was recrystallized from water to afford 25.2 g (63%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH3:14])[CH2:11][C:12]#N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C(OCC)=[O:26].[Cl-].[NH4+]>C1(C)C=CC=CC=1.CCCCCC>[CH2:1]([O:8][CH2:9][CH:10]([CH3:14])[CH2:11][CH:12]=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC=O
Reactant: CC(CC#N)COCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(CC=O)COCc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 5.8 g. (0.0307 mole) of rac. 4-benzyloxy-3-methylbutyronitrile in 290 ml. of hexane was stirred at -65° C. to -70° C. while 22.4 ml. (4.78 g.; 0.0337 mole) of 25% diisobutylaluminum hydride solution in toluene was added dropwise. Theresulting solution was stirred at -65° C. to -70° C. for 0.5 hours then at room temperature for 5 hours whereupon 2.8 ml. of ethyl formate was added dropwise. The reaction mixture was then treated with 250ml. of saturated aqueous ammonium chloride solution. Stirring was continuedfor 20 minutes at which point 125 ml. of 5% by weight aqueous sulfuric acidwas added and stirring was continued for an additional 10 minutes. The organic layer was separated and the aqueous layer was extracted with ether. The organic solutions were combined and processed as in Example 1 giving 4.79 g. (81.3%) of rac. 4-benzyloxy-3-methylbutanal as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[CH:4]=[C:5]([F:25])[C:6]2[N:7]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:8]3[C:13]([S:14][C:15]=2[CH:16]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=3.C1(C)C=CC=CC=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH:86]1[CH2:91][CH2:90][O:89][CH2:88][CH2:87]1>>[CH3:1][N:2]([CH3:26])[C:3]1[CH:4]=[C:5]([F:25])[C:6]2[N:7]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:8]3[C:13]([S:14][C:15]=2[CH:16]=1)=[CH:12][C:11]([N:86]1[CH2:91][CH2:90][O:89][CH2:88][CH2:87]1)=[CH:10][CH:9]=3
Reactant: CN(C)c1cc(F)c2c(c1)Sc1cc(Br)ccc1N2C(=O)OC(C)(C)C
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CN(C)c1cc(F)c2c(c1)Sc1cc(N3CCOCC3)ccc1N2C(=O)OC(C)(C)C

Procedure:
To a stirred solution of 3-dimethylamino-1-fluoro-7-bromo-10-Boc-phenothiazine (14) (200 mg, 0.45 mmol) in toluene (10 mL) Pd(dba)2 (14.4 mg, 0.025 mmol), BINAP (10.9 mg, 0.018 mmol), Cs2CO3 (326 mg, 1.0 mmol) and morpholine (87 mg, 1.0 mmol) were added. The mixture was refluxed for 24 h. After that reaction mixture was filtered, solvent was removed under vacuum. Product was used without additional purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].C(=O)([O-])[O-].[K+].[K+].[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][S:24](Cl)(=[O:26])=[O:25])([O-:16])=[O:15]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[OH:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][S:24]([CH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N+:14]([O-:16])=[O:15])(=[O:25])=[O:26]
Reactant: O=[N+]([O-])c1ccccc1CS(=O)(=O)Cl
Reactant: NCCOCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccccc1CS(=O)(=O)NCCOCCO
Reaction time: 8 h

Procedure:
To a stirred solution of 2-(2-aminoethoxy)ethanol (0.557 g), 5.31 mmol) and potassium carbonate (1.17 g, 8.48 mmol) in toluene (50 ml) and water (4 ml) at room temperature, was added 2-nitro-alpha-toluenesulfonyl chloride (1.00 g, 4.24 mmol) in one portion and the reaction was left to stir overnight. The reaction was diluted with ethyl acetate and water. The organic layer was separated before being washed with brine, dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo. The crude material was purified by column chromatography eluting with ethyl acetate:hexane to afford N-[2-(2-hydroxyethoxy)ethyl]-1-(2-nitrophenyl)methanesulfonamide as product (0.155 g, 12%); Rf (ethyl acetate:hexane 2:1) 0.11; δH (400 MHz, CDCl3) 8.02 (1H, d), 7.67 (2H, m), 7.53 (1H, dt), 5.15 (1H, brs), 4.86 (2H, s), 3.71 (2H, s), 3.56 (4H, m), 3.19 (2H, m) and 2.36 (1H, s); LCMS Rt=2.60 min, m/z (APCI) 305 (MH+).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4]([O:14][C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=[O:17])=[CH:3][CH:2]=1.[CH2:21](O)[CH3:22]>>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4]([O:14][C:15]([CH3:20])([CH3:19])[C:16]([O:18][CH2:21][CH3:22])=[O:17])=[CH:3][CH:2]=1
Reactant: CC(C)(Oc1cccc2c1sc1ccccc12)C(=O)O
Reactant: CCO
Product: CCOC(=O)C(C)(C)Oc1cccc2c1sc1ccccc12

Procedure:
2-(4-Dibenzothiophenoxy)-2-methylpropionic acid (9.5 g) was dissolved in 500 ml absolute ethanol. Dry hydrogen chloride was bubbled through for 3 hours, and the mixture was stored over night. After evaporation of the solvent, the residue was dissolved in 250 ml ether, washed with sodium bicarbonate solution, dried and evaporated to give 8.5 g of a brown liquid, b.p. 155-170/0.001 mm Hg.
Reaction SMILES: [C:1]([C:3]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[C:12]([C:21]([NH:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[O:22])[C:13](=[O:20])[N:14]3[C:19]=2[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH2:5][CH2:4]1)#[N:2].C(N(CC)CC)C.Cl[C:44]([O:46][CH3:47])=[O:45]>ClCCl>[C:1]([C:3]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[C:12]([C:21]([NH:23][CH:24]3[CH2:29][CH2:28][N:27]([C:44]([O:46][CH3:47])=[O:45])[CH2:26][CH2:25]3)=[O:22])[C:13](=[O:20])[N:14]3[C:19]=2[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH2:5][CH2:4]1)#[N:2]
Reactant: COC(=O)Cl
Reactant: N#CC1(c2ccccn2)CCN(Cc2cc(C(=O)NC3CCNCC3)c(=O)n3ccccc23)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CCC(NC(=O)c2cc(CN3CCC(C#N)(c4ccccn4)CC3)c3ccccn3c2=O)CC1
Reaction time: 1 h

Procedure:
To a solution of 1-[(4-cyano-4-pyridin-2-ylpiperidin-1-yl)methyl]-4-oxo-N-piperidin-4-yl-4H-quinolizine-3-carboxamide (0.027 g, 0.057 mmol) in 2 mL of dichloromethane was added triethylamine (0.3 mL, 2.1 mmol) followed by methyl chloroformate (0.10 mL, 1.3 mmol). After 1 h, the mixture was washed with 0.5 N aqueous sodium hydroxide and brine, dried over sodium sulfate, filtered, and concentrated in vacuo to provide the title compound that gave a proton NMR spectra consistent with theory: 1H NMR (400 MHz, CDCl3) δ 9.80 (d, J=7.7 Hz, 1H), 9.40 (d, J=7.3 Hz, 1H), 8.65 (s, 1H), 8.60-8.58 (m, 1H), 8.19 (d, J=8.9 Hz, 1H), 7.76-7.66 (m, 2H), 7.62-7.59 (m, 1H), 7.32-7.23 (m, 2H), 4.24-4.21 (m, 1H), 4.03 (br s, 1H), 3.82 (s, 2H), 3.71 (s, 3H), 3.69-3.61 (m, 2H), 3.15-3.09 (m, 1H), 3.02-2.98 (m, 1H), 2.60-2.57 (m, 1H), 2.55-2.50 (m, 2H), 2.32-2.25 (m, 1H), 2.09-2.02 (m, 2H), 1.93 (br s, 1H), 1.59-1.52 (m, 1H), 1.40-1.37 (m, 2H), 1.06-1.01 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][NH2:13].C([O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[C:42]3[C:37](=[CH:38][C:39]([C:43](O)=[O:44])=[CH:40][CH:41]=3)[C:36]([CH3:46])=[C:35]2[CH3:47])=[CH:29][CH:28]=1)=[O:20])(C)(C)C>>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][NH:13][C:43]([C:39]1[CH:38]=[C:37]2[C:42](=[CH:41][CH:40]=1)[N:34]([CH2:33][C:30]1[CH:29]=[CH:28][C:27]([C:22]3[C:21]([C:19]([OH:20])=[O:18])=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:32][CH:31]=1)[C:35]([CH3:47])=[C:36]2[CH3:46])=[O:44]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: NCc1ccc(C(F)(F)F)cc1F
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3ccc(C(F)(F)F)cc3F)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (2-fluoro-4-(trifluoromethyl)phenyl)methanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 575 [M+H]+.