Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([N:17]([CH3:19])[CH3:18])[CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[O:16])=[CH:5][CH:4]=1.N.[CH2:21]([Mg][Cl:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>O1CCCC1.O>[ClH:29].[CH2:21]([C:11]1([OH:16])[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]1[CH:9]([C:6]1[CH:5]=[CH:4][C:3]([Br:2])=[CH:8][CH:7]=1)[N:17]([CH3:19])[CH3:18])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CN(C)C(c1ccc(Br)cc1)C1CCCCC1=O
Reactant: Cl[Mg]Cc1ccccc1
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(c1ccc(Br)cc1)C1CCCCC1(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 35.9 %

Procedure:
The base was freed from the 2.0 g (5.77 mmole) of the hydrochloride of 2-[(4-bromophenyl)dimethylaminomethyl]cyclohexanone obtained according to stage 1 with 20 ml of water and 5 ml of ammonia solution (25 vol. %), extracted three times with 20 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator without heating (500 to 10 mbar). 1.70 g (5.5 mmole) of this base were dissolved in 8.5 ml of tetrahydrofuran, added dropwise while cooling in an ice bath to 3.3 ml (6.6 mmole) of benzylmagnesium chloride (2 M solution in tetrahydrofuran), and stirred for 15 hours at RT. The reaction mixture was worked up by adding 10 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 10 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 1.91 g of crude base (86.64% of theory) were obtained, from which 0.86 g of 1-benzyl-2-[(4-bromophenyl) dimethylaminomethyl]cyclohexanol, hydrochloride (35.9% of theory) were obtained according to the procedure described in Example 1 (3rd Stage) with chloro-trimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 151° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[C@H:12]([OH:15])[CH2:13][OH:14].N1C=CC=CC=1.[C:22](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:22]([O:14][CH2:13][C@H:12]([C:3]1[C:4]([CH3:11])=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Br:1])[OH:15])(=[O:23])[C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc([N+](=O)[O-])cc(Br)c1[C@H](O)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])cc(Br)c1[C@H](O)COC(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 76.6 %

Procedure:
To a suspension of (S)-1-(2-Bromo-6-methyl-4-nitrophenyl)ethane-1,2-diol (17.0 g, 61.6 mmol) in DCM (435 mL) at 0° C. was added pyridine (18.6 g, 235.4 mmol) and PivCl (13.4 g, 110.8 mmol) slowly. After stirring at 0° C. for 5 min, the system was raised to room temperature and stirred at this temperature for 5 h. TLC showed the reaction was complete. The reaction mixture was treated with saturated aqueous NaHCO3 (500 mL), and the resulting system was extracted with DCM (2×200 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, concentrated in vacuum, and purified by silica gel column (Petroleum Ether:EtOAc (30:1)) to afford (S)-2-(2-Bromo-6-methyl-4-nitrophenyl)-2-hydroxyethyl pivalate (17 g, 77%) as yellow solid. 1H-NMR: 400 MHz, (CDCl3) δ: 8.28 (s, 1H), 8.00 (d, J=2.0 Hz, 1H), 5.70-5.66 (m, 1H), 4.58-4.53 (m, 1H), 4.31-4.26 (m, 1H), 2.84 (d, J=5.6 Hz), 2.68 (s, 3H), 1.22 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:16]([CH3:17])=[C:15]([Cl:18])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:12])[C:10]=1[OH:11])=[O:5].C1C=CC=CC=1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(N(CC)CC)C>[Cl:1][C:2]1[C:16]([CH3:17])=[C:15]([Cl:18])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:12])[C:10]=1[O:11][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:5]
Reactant: BrCc1ccccc1
Reactant: Cc1c(Cl)ccc(C(=O)c2cnn(C)c2O)c1Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1c(Cl)ccc(C(=O)c2cnn(C)c2OCc2ccccc2)c1Cl
Reaction time: 2 h
Yield: 89 %

Procedure:
1.43 g (0.005 mol) of 4-(2,4-dichloro-3-methylbenzoyl)-1-methyl-5-hydroxypyrazole was dissolved in 20 ml of benzene containing 0.50 g (0.005 mol) of triethylamine, and 0.86 g (0.005 mol) of benzylbromide was added thereto. Then, the reaction mixture was refluxed with stirring for 2 hours. After cooling, the precipitated salt was filtered off, and benzene was distilled off from the residual solution under reduced pressure. The resulting oily product was purified through a silica gel column chromatography (eluent:benzene) to obtain 1.67 g of the title compound (yield 89%).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][CH2:15][C:16](Cl)=[O:17].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:14][CH2:15][C:16]([O:13][C@@H:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C@H:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:17]
Reactant: O=C(Cl)CCl
Reactant: O[C@@H]1CCCC[C@H]1c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CCl)O[C@@H]1CCCC[C@H]1c1ccccc1

Procedure:
In the next step, (±)-trans-2-phenylcyclohexanol is reacted with chloroacetyl chloride at reflux in a basic solvent such as a mixture of methylene chloride and pyridine or, more preferably, 4-dimethylaminopyridine and methylene chloride. The resulting (±)-trans-2-phenylcyclohexyl chloroacetate of the formula ##STR29## can be isolated by conventional means such as extraction followed by distillation of the organic layer.
Reaction SMILES: CCCP(O)(O)=O.CCN(C(C)C)C(C)C.[CH2:17]([O:19][P:20]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[N:38]=[C:37]([NH:39][C:40]3[CH:41]=[CH:42][C:43]([C@@H:51]4[CH2:56][CH2:55][C@H:54]([C:57]([OH:59])=O)[CH2:53][CH2:52]4)=[C:44]4[C:48]=3[C:47](=[O:49])[N:46]([CH3:50])[CH2:45]4)[C:36]([C:60]([F:63])([F:62])[F:61])=[CH:35][N:34]=2)=[C:28]([O:64][CH3:65])[CH:27]=1)([O:22][CH2:23][CH3:24])=[O:21])[CH3:18].Cl.[NH2:67][OH:68]>CN(C=O)C>[OH:68][NH:67][C:57]([C@@H:54]1[CH2:55][CH2:56][C@H:51]([C:43]2[CH:42]=[CH:41][C:40]([NH:39][C:37]3[C:36]([C:60]([F:63])([F:61])[F:62])=[CH:35][N:34]=[C:33]([NH:32][C:29]4[CH:30]=[CH:31][C:26]([CH2:25][P:20](=[O:21])([O:19][CH2:17][CH3:18])[O:22][CH2:23][CH3:24])=[CH:27][C:28]=4[O:64][CH3:65])[N:38]=3)=[C:48]3[C:44]=2[CH2:45][N:46]([CH3:50])[C:47]3=[O:49])[CH2:52][CH2:53]1)=[O:59]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@@H](C(=O)O)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Reactant: NO
Agent: CCCP(=O)(O)O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@@H](C(=O)NO)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 50% 1-propylphosphonic acid cyclic anhydride in DMF (9.9 μL, 0.017 mmol) were added additional DMF (0.5 mL), DIPEA (9.9 μL, 0.0567 mmol) and cis-4-(7-{[2-({4-[(diethoxyphosphoryl)methyl]-2-methoxyphenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)cyclohexanecarboxylic acid (10.0 mg, 0.0142 mmol). The mixture was stirred at room temperature for 30 minutes. Hydroxylamine hydrochloride (2.0 mg, 0.0283 mmol) was added and the mixture was stirred at room temperature overnight. The crude mixture was purified by MDP to obtain the title compound (5.2 mg, 51% yield). 1H NMR (400 MHz, methanol-d4) d ppm 1.29 (t, J=7.1 Hz, 6H), 1.68-1.82 (m, 4H), 2.00-2.16 (m, 4H), 2.52 (br. s., 1H), 2.73 (t, J=11.1 Hz, 1H), 3.19 (s, 3H), 3.38 (d, J=21.7 Hz, 2H), 3.90 (s, 3H), 4.11 (qd, J=7.3, 7.1 Hz, 4H), 4.55 (s, 2H), 6.95-7.04 (m, 1H), 7.14 (s, 1H), 7.39 (br. s., 1H), 7.65 (d, J=8.1 Hz, 1H), 8.33 (br. s., 2H). MS (ES+): m/z 721.19 (100) [MH+]; HPLC: tR=0.97 min (UPLC, purity).
Reaction SMILES: CO.[CH3:3][C:4]1([CH3:15])[CH2:9][CH2:8][CH2:7][C:6]([C:10]#[C:11][CH2:12][CH:13]=[CH2:14])=[CH:5]1>O>[CH3:3][C:4]1([CH3:15])[CH2:9][CH2:8][CH:7]=[C:6]([C:10]#[C:11][CH2:12][CH:13]=[CH2:14])[CH2:5]1
Reactant: C=CCC#CC1=CC(C)(C)CCC1
Solvent: CO
Solvent: O
Product: C=CCC#CC1=CCCC(C)(C)C1
Yield: 70 %

Procedure:
(c') 7 g of the above prepared carbinol were heated in a distillation apparatus in the presence of 2 g of H3BO3 at 12 Torr until no further formation of water was observed. The temperature was then slowly increased to 120°-130° and a 2:3 mixture of 1-(3,3-dimethyl-cyclohex-1-en-1-yl)-pent-4-en-1-yne and 1-(3,3-dimethyl-cyclohex-6-en-1-yl)-pent-4-en-1-yne was obtained (5.3 g; 70% yield). The subsequent conversion to the desired cyclohexenic ketones is effected according to the procedure given above (pathway I) paragraph d)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Cl[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([CH2:19]Cl)[C:13]=1[OH:21].[Cl-].[Al+3].[Cl-].[Cl-].ClCCl>[N+](C1C=CC=CC=1)([O-])=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:9])=[C:7]([CH:8]=1)[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([CH2:19][C:5]2[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][C:6]=2[OH:9])[C:13]=1[OH:21])#[N:2]
Reactant: N#Cc1ccc(O)cc1
Reactant: Oc1c(CCl)cc(F)cc1CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: ClCCl
Product: N#Cc1ccc(O)c(Cc2cc(F)cc(Cc3cc(C#N)ccc3O)c2O)c1
Temperature: 0 °C
Reaction time: 14 h
Yield: 3 %

Procedure:
p-Cyanophenol (19.4 g) and 2,6-bis(chloromethyl)-4-fluorophenol (17.0 g) were dissolved in nitrobenzene (250 ml) at 20°. The solution was cooled to 10° and crushed aluminium chloride (anhydrous 65 g) was added in 5 g portions over two hours. During the addition the temperature was maintained at 10°-12°. Stirring was continued at 20° for 14 hrs. The viscous black mixture was poured onto a vigorously stirred mixture of ice (2 l) and dichloro methane (2 l). The organic solvent layer was dried, dichloro methane and nitrobenzene removed by vacuum distillation and the residual tar passed through a silica column. The product, 2,6-bis(5-cyano-2-hydroxybenzyl)-4-fluorophenol (mp 222°) was obtained in 3% yield.
Reaction SMILES: [BH4-].[Na+].[OH-].[Na+].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[NH:17][CH:16]([C:18]([OH:20])=[O:19])[CH2:15][S:14]2)=[CH:9][CH:8]=1.C(O)(=O)C>C([O-])([O-])=O.[K+].[K+]>[SH:14][CH2:15][CH:16]([NH:17][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[CH:12][CH:11]=1)[C:18]([OH:20])=[O:19]
Reactant: COc1ccc(C2NC(C(=O)O)CS2)cc1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: CC(=O)O
Product: COc1ccc(CNC(CS)C(=O)O)cc1
Temperature: 2.5 °C
Yield: 68.1 %

Procedure:
A 22 L three-necked round bottom flask fitted with an internal temperature probe and a mechanical stirrer was charged with sodium borohydride (221.3 g, 5.85 mol). A 1.75 L portion of 0.25 M sodium hydroxide was added and the mixture was stirred until homogeneous. The solution was cooled to 0-5° C. 2-(4-methoxyphenyl)-thiazolidine-4-carboxylic acid (350.0 g, 1.46 mol) was dissolved in 2.1 L of a 0.62 M K2CO3 aqueous solution. The resulting solution was added to the solution of sodium borohydride while maintaining an internal temperature of below 30° C. The reaction was stirred until HPLC analysis showed no remaining starting material (approximately 1 hour). The reaction was cooled to 0° C. and 700 mL of glacial acetic acid was added with stirring. The final pH of the reaction mixture was approximately 5. The resulting white solid was filtered, washed with 3 L of water and 2.5 L of ethanol, and dried in a vacuum oven at 50° C. for 12 hours. Approximately 240 g of 3-mercapto-2-(4-methoxy-benzylamino)-propionic acid was obtained (68% yield). 1H NMR (300 MHz, DMSO) δ 7.32 (d, 8.9 Hz, 2H), 6.91 (d, 8.9 Hz, 2H), 3.87 (AB, JAB=13.1 Hz, ΔvAB=18.5 Hz, 2H), 3.72 (s, 3H), 3.24 (dd, J=5.3, 5.3 Hz, 1H), 2.76 (d, J=5.7 Hz, 2H).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:18][C@H:17]([O:19][C:20](=[O:22])[CH3:21])[C@@H:16]([CH3:23])[O:15][C@:6]1([NH:24][C:25](=[O:35])[CH2:26][P:27]([O:32][CH2:33][CH3:34])([O:29][CH2:30][CH3:31])=[O:28])[O:7]CC1C=CC=CC=1)(=[O:3])[CH3:2].C(O)C>[Pd].C(O)=O>[C:1]([O:4][C@H:5]1[CH2:18][C@H:17]([O:19][C:20](=[O:22])[CH3:21])[C@@H:16]([CH3:23])[O:15][C:6]1([NH:24][C:25](=[O:35])[CH2:26][P:27]([O:29][CH2:30][CH3:31])([O:32][CH2:33][CH3:34])=[O:28])[OH:7])(=[O:3])[CH3:2]
Reactant: CCOP(=O)(CC(=O)N[C@]1(OCc2ccccc2)O[C@H](C)[C@@H](OC(C)=O)C[C@@H]1OC(C)=O)OCC
Agent: [Pd]
Solvent: O=CO
Solvent: CCO
Product: CCOP(=O)(CC(=O)NC1(O)O[C@H](C)[C@@H](OC(C)=O)C[C@@H]1OC(C)=O)OCC

Procedure:
Crude benzyl 2,4-di-O-acetyl-3,6-dideoxydiethylphosphonoacetamido-alpha-D-mannopyranoside, 21, ethanol (10 ml), 2 88% formic acid and 0.1 g Pd black were heated at reflux overnight under argon with stirring. The reaction mixture was filtered and evaporated to dryness, and the residue was chromatographed on SiO2 (40 g; dichloromethane-methanol 95:5) to afford 0.57 g 2,4-di-O-acetyl-3,6-dideoxydiethylphosphonoacetamido-D-mannopyranose, as a yellow oil.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH3:11])=[CH:5][CH:4]=1.[O:12]1[C:16]2([CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1.[Cl-].[NH4+]>C1COCC1>[CH2:9]([C:6]1[CH:7]=[CH:8][C:3]([CH:19]2[CH2:20][CH2:21][C:16]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:17][CH2:18]2)=[CH:4][CH:5]=1)[CH2:10][CH3:11]
Reactant: CCCc1ccc(Br)cc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCc1ccc(C2CCC3(CC2)OCCO3)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
Well-dried magnesium (14.5 g) and THF (100 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and heated to 40° C. 1-Bromo-4-propylbenzene (s14) (100.0 g) dissolved in THF (300 ml) was added dropwise in the temperature range of 40° C. to 60° C., and the stirring was continued for another 60 minutes. 1,4-Dioxaspiro[4.5]decan-8-one (s7) (78.4 g) dissolved in THF (150 ml) was slowly added dropwise in the temperature range of −5° C. to 0° C., and the stirring was continued for another 60 minutes. After the reaction mixture was allowed to come to room temperature, it was treated with an aqueous solution of ammonium chloride (3%), and the aqueous layer was extracted with toluene. The combined organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was mixed with p-toluenesulfonic acid (3.9 g) and toluene (300 ml), and the mixture was heated to reflux for 2 hours while distilled water was removed. After the reaction mixture had been cooled to 30° C., it was treated with water, and the aqueous layer was extracted with toluene. The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder. The purified product was dissolved in a mixed solvent of toluene (250 ml) and Solmix A-11 (250 ml), to which Pd/C (5.0 g) was added. The mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the reaction had been completed, Pd/C was removed, and then solvent was distilled off. The residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder, and then by recrystallization from heptane to give 8-(4-propylphenyl)-1,4-dioxaspiro[4.5]decane (s15) (68.0 g). The yield based on the compound (s14) was 52.0%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[C:5]([CH3:10])=[CH:4][C:3]=1[NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.[O:25]1CCC[CH2:26]1>>[C:8]([C:6]1[C:5]([CH3:10])=[CH:4][C:3]2[N:11]([CH:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]3)[C:26](=[O:25])[NH:1][C:2]=2[CH:7]=1)#[N:9]
Reactant: C1CCOC1
Reactant: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)cc1C#N
Product: Cc1cc2c(cc1C#N)[nH]c(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Yield: 100 %

Procedure:
A solution of 1,1-dimethylethyl 4-[(2-amino-4-cyano-5-methylphenyl)amino]-1-piperidinecarboxylate (D92) (2.55 mmol, 840 mg) in tetrahydrofuran (8 mL) was treated with N,N′-carbonyldiimidazole (3.83 mmol, 613 mg, 1.5 eq) under argon at room temperature, then the mixture was heated at 50° C. for 1 h, concentrated under reduced pressure, and the residue was treated with 10% aqueous sodium carbonate solution and extracted twice with ethyl acetate. The organics were combined, dried and concentrated under reduced pressure to give the title compound (3.23 mmol, 1.15 g, >100% yield). M+H 357.3, 301.2 (full molecule and fragment for loss of the tert-butyl group).
Reaction SMILES: [CH3:1][C:2]1([CH2:15][C:16]([NH2:18])=[O:17])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.F[B-](F)(F)F.[CH2:24]([O+](CC)CC)[CH3:25]>C(Cl)Cl>[CH2:24]([O:17][C:16](=[NH:18])[CH2:15][C:2]1([CH3:1])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:25]
Reactant: CC[O+](CC)CC
Reactant: CC1(CC(N)=O)OCCc2c1[nH]c1ccccc21
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC(=N)CC1(C)OCCc2c1[nH]c1ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-Methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide (20.0 g., 0.817 mole), described in Example 126, is dissolved in dry methylene chloride (400 ml) and freshly prepared triethyloxonium fluoroborate (17.00 g., 0.894 mole) is added in one portion to the solution. The reaction mixture is stirred at room temperature for 2 hr. The methylene chloride solution is washed with cold 30% aqueous potassium carbonate followed by brine and the dried organic layer is concentrated under reduced pressure. The residue is dissolved in ether (150 ml.). The solution is filtered and crystallization proceeds at room temperature to afford ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetimidate, m.p. 139.5°-141° C.
Reaction SMILES: CN(C)CCO.[Li].[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[N:9]=1.[F:31][C:32]1[N:43]=[CH:42][CH:41]=[CH:40][C:33]=1[C:34](N(OC)C)=[O:35]>C1COCC1>[F:31][C:32]1[N:43]=[CH:42][CH:41]=[CH:40][C:33]=1[C:34]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([N:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]2)[N:9]=1)=[O:35]
Reactant: CON(C)C(=O)c1cccnc1F
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3ccccc3cn2)CC1
Agent: CN(C)CCO
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2cc3ccccc3c(C(=O)c3cccnc3F)n2)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 7.6 %

Procedure:
A solution of 2-dimethylaminoethanol (0.072 ml, 0.72 mmol) in hexanes (3 ml) was cooled down to −40° C. A 2.5M solution of nbutyl lithium in tetrahydrofuran (0.574 ml, 1.44 mmol) was added dropwise. The solution was stirred for 20 minutes. A suspension of tert-butyl 4-(isoquinolin-3-yl)piperazine-1-carboxylate (0.75 mg, 0.24 mmol) in hexanes (8 ml) was added and the resulting solution was stirred for 1 hour. The solution was cooled down to −78° C. A solution of 2-fluoro-N-methoxy-N-methylnicotinamide (176.3 mg, 0.96 mmol) in THF (40 ml) was added dropwise. The reaction mixture was warmed up to −50° and stirred for 1 hour, then the mixture was stirred at 0° C. for a further 1 hour. The crude mixture was partitioned between water and ethyl acetate. The organic extract was dried over magnesium sulfate, filtered and concentrated under vacuo. The residue was and purified on silica gel by flash column chromatography to give the title compound as a yellow oil (8 mg, 8% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.CN(C=O)C.C(Cl)(=O)C([Cl:21])=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([Cl:21])=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)Cc1cc(F)cc(F)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
3,5-Difluorophenylacetic acid (30 g, 0.174 mol) (Aldrich) was dissolved in dichloromethane and this solution was cooled to 0° C. DMF (0.5 mL, catalytic) was added followed by the dropwise addition of oxalyl chloride (18 mL, 0.20 mol) over a 5 minute period. The reaction was stirred for 3 h and then rotoevaporated at reduced pressure to give an oil which was placed on a high vacuum pump for 1 h to afford 3,5-difluorophenylacetyl chloride as a thin yellow oil. Other acid chlorides can be prepared in a similar manner.
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[O:15][CH2:14][C:13]([CH3:18])([CH3:17])[C:12]=2[CH:11]=[C:10](Br)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])(C)(C)C.CCCCC.[B:30](OC)([O:33]C)[O:31]C>O1CCCC1>[CH2:1]([C:8]1[C:16]2[O:15][CH2:14][C:13]([CH3:18])([CH3:17])[C:12]=2[CH:11]=[C:10]([B:30]([OH:33])[OH:31])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COB(OC)OC
Reactant: CC1(C)COc2c(Cc3ccccc3)cc(Br)cc21
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC1(C)COc2c(Cc3ccccc3)cc(B(O)O)cc21

Procedure:
Following General Procedure A and using 7-benzyl-5-bromo-3,3-dimethyl-2,3-dihydro-benzofuran (Intermediate 39, 1.57 g, 4.81 mmol), 15 mL of anhydrous tetrahydrofuran, 1.7M solution of t-butyllithium in n-pentane (5.64 mL, 9.6 mmol) and trimethyl borate (1.02 mL, 9.6 mmol), the title compound was obtained as a foam that was used as such for the next step without purification and characterization.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9]O)=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1.P([O-])(OC1C=CC=CC=1)OC1C=CC=CC=1>>[O:7]([CH2:8][CH2:9][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1)[C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: OCCOc1ccccc1
Reactant: Cc1cccc(N)c1
Agent: [O-]P(Oc1ccccc1)Oc1ccccc1
Product: Cc1cccc(NCCOc2ccccc2)c1
Yield: 85 %

Procedure:
138 parts of phenylglycol, 214 parts of m-toluidine and 15 parts of diphenyl phosphite are mixed whilst stirring. The reaction is carried out using the method described in Example 9. 193 parts of N-(2-phenoxyethyl)-m-toluidine, corresponding to a yield of 85% of theory, are obtained at a boiling point of 186° - 192° C/5 mm Hg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.N1CCCC1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C:18]1=[O:26].Cl>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:17][C:18]1=[O:26]
Reactant: COc1ccc(C=O)cc1Br
Reactant: O=C1Cc2ccccc2N1
Agent: Cl
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: COc1ccc(C=C2C(=O)Nc3ccccc32)cc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 41 %

Procedure:
A mixture of 3-bromo-p-anisaldehyde (1 g, 4.65 mmol), pyrrolidine (1.9 ml, 23.2 mmol) and oxindole (0.62 g, 4.65 mmol) in dimethylformamide (7 ml) was held in a sealed tube at 100° C. for 12 hours. The mixture was cooled to room temperature and poured into 1N hydrochloric acid (100 ml). The precipitate which formed was filtered and washed with water. The precipitate was then dissolved in ethyl acetate (200 ml), the solution washed with brine, dried over magnesium sulfate and then concentrated. The solid obtained was chromatographed (silica, 30-40% ethyl acetate/hexanes) to give 0.63 g (42%) of 3-(3-bromo-4-methoxybenzylidene)-1,3-dihydroindol-2-one as a yellow solid.