Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:36](O)(=[O:38])[CH3:37].N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[C:36]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1)(=[O:38])[CH3:37]
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](O)C1
Reactant: CC(=O)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)O[C@H]1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 22-L, 3 neck round bottom flask equipped with a mechanical stirrer, thermocouple, addition funnel and nitrogen bubbler was charged with 422 g (1.91 mol) of benzyl (3R)-3-hydroxypyrrolidine-1-carboxylate (Intermediate 1, Step A), 12 L of toluene, 751 g (2.86 mol) of triphenylphosphine, and 164 mL (2.86 mol) of glacial acetic acid. The resultant mixture was stirred at ambient temperature and then 500 g (2.87 mol) of diethyl azodicarboxylate was added via the addition funnel over a period of about 30 min, keeping the internal temperature <28° C. with a cold water bath. The reaction was stirred at ambient temperature overnight. The solvent was removed in vacuo and the residue was triturated with 6 L of diethyl ether. The solid was filtered off and washed well with diethyl ether. The filtrate and ether washings were combined and concentrated to a thick yellow oil with solids. Purification by flash chromatography (silica gel, eluting sequentially with 5% and a gradient of 10% to 30% ethyl acetate/hexane) gave the title compound as a pale yellow oil.
Reaction SMILES: [FH:1].N[C:3]1[C:4]([Cl:10])=[N:5][CH:6]=[C:7]([Cl:9])[CH:8]=1.N([O-])=O.[Na+]>CN(C)C=O>[Cl:10][C:4]1[C:3]([F:1])=[CH:8][C:7]([Cl:9])=[CH:6][N:5]=1
Reactant: F
Reactant: Nc1cc(Cl)cnc1Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc(Cl)cnc1Cl
Reaction time: 2 h
Yield: 91.3 %

Procedure:
A 500 ml polytetrafluoroethylene reactor equipped with stirrer, thermometer and reflux condenser is charged with 120 g of hydrogen fluoride. A solution of 40.7 g (0.25 mol) of 3-amino-2,5-dichloropyridine in 100 ml of dimethylformamide is added dropwise at a temperature in the range from 0° C. to +10° C. Then 20.7 g (0.3 mol) of sodium nitrite are introduced into this solution at 55° C. The resultant nitrogen is removed from the reactor through the reflux condenser. Gas evolution ceases after 2 hours at +50° C. 150 ml of methylene chloride are added to the reaction mixture wich is then poured into ice water. The two-phase mixture is neutralized with concentrated ammonia solution. The organic phase is separated and the aqueous phase is extracted several times with methylene chloride. The combined organic phases are dried over sodium sulfate and concentrated by evaporation. The crude product is purified by distillation, affording 37.9 g (91.4% of theory) of 2,5-dichloro-3-fluoropyridine.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][C:15]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)([OH:18])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH2:32][C:33]1[N:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][N:34]=1>>[NH2:32][C:33]1[N:38]=[CH:37][C:36]([C:2]2[N:3]=[C:4]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][C:15]([C:19]5[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=5)([OH:18])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:35][N:34]=1
Reactant: OC1(c2ccc(Cl)cc2)CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCC(O)(c5ccc(Cl)cc5)CC4)cc3n2)cn1
Yield: 46.7 %

Procedure:
1-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-4-(4-chloro-phenyl)-piperidin-4-ol (146 mg, 0.30 mmol) was reacted with 2-amino-pyrimidine-5-boronic acid pinacol ester (94 mg, 0.45 mmol) in General Procedure A. After extraction into 2M HCl, the mixture was washed with EtOAc then made basic and the precipitate collected by filtration. Purification on silica gave 421 as a pale yellow solid (75 mg, 0.14 mmol). NMR (CD3OD, 400 MHz), 9.19 (s, 2H); 7.52 (m, 2H); 7.39 (s, 1H), 7.35 (m, 2H); 4.08 (t, 4H, J=4.1 Hz); 3.97 (s, 2H); 3.89 (t, 4H, J=4.8 Hz); 2.87 (d, 2H); 2.70 (t, 2H, J=11.2 Hz); 2.18 (m, 2H); 1.77 (d, 2H, J=13.2 Hz) MS: (ESI+): MH+=538.27
Reaction SMILES: [H-].[Na+].[C:3]([CH:5]1[C:14]2[C:9](=[C:10]([Cl:16])[CH:11]=[CH:12][C:13]=2[Cl:15])[C:7](=[O:8])[O:6]1)#[N:4].[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21](S(C)(=O)=O)[N:20]=1>>[C:3]([C:5]1([C:21]2[N:22]=[C:23]([O:25][CH3:26])[CH:24]=[C:19]([O:18][CH3:17])[N:20]=2)[C:14]2[C:9](=[C:10]([Cl:16])[CH:11]=[CH:12][C:13]=2[Cl:15])[C:7](=[O:8])[O:6]1)#[N:4]
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: N#CC1OC(=O)c2c(Cl)ccc(Cl)c21
Agent: [H-]
Agent: [Na+]
Product: COc1cc(OC)nc(C2(C#N)OC(=O)c3c(Cl)ccc(Cl)c32)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.5 %

Procedure:
21.5 g of NaH in oil dispersion are added to 112.75 g of 3-cyano-4,7-dichlorophthalide and 96.7 g of 4,6-dimethoxy-2-methylsulfonyl-pyrimidine. (The hydride is washed with hexane, the hexane removed by suction and the residue covered with DMF and cooled it an ice bath.) The reaction mixture is left to stir overnight at RT and the solution then poured into 3 L of water containing 15 ml of conc. H2SO4 and stirred mechanically until a viscous gum formed around the stirred blade. The water layer is decanted and extracted with 3×400 ml of toluene, the first two extracts added to the gum and the mixture stirred until the gum dissolved. The toluene solution is washed 2×100 ml of water and 1×100 ml of toluene and the combined toluene layers dried over Na2SO4 concentrated to 400 ml and left to stand overnight. The still homogeneous solution is flash-chromatographed over silica gel with toluene (250 ml fraction 5) fractions 5-9 are combined and stripped to give 30 g of the title product m.p. 123°-126° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([O:33][C:34]([C@H:36]1[CH2:41][CH2:40][C@H:39]([C:42](O)=[O:43])[CH2:38][CH2:37]1)=[O:35])C1C=CC=CC=1.C(C1C=C(NC(C2C=CC(N3CCN(C([C@H]4CCC[C@@H]4C(O)=O)=O)CC3)=NC=2)=O)C=CC=1)(C)(C)C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:42]([CH:39]4[CH2:38][CH2:37][CH:36]([C:34]([OH:35])=[O:33])[CH2:41][CH2:40]4)=[O:43])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[O:25])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCNCC3)cc2)c1
Reactant: O=C(O)[C@H]1CC[C@H](C(=O)OCc2ccccc2)CC1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(C(=O)[C@H]4CCC[C@@H]4C(=O)O)CC3)nc2)c1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(C(=O)C4CCC(C(=O)O)CC4)CC3)cc2)c1

Procedure:
4-{4-[4-(3-tert-Butyl-phenylcarbamoyl)-phenyl]-piperazine-1-carbonyl}-cyclohexanecarboxylic acid was prepared from N-(3-tert-butyl-phenyl)-4-piperazin-1-yl-benzamide and trans-1,4-cyclohexane dicarboxylic acid monobenzyl ester in a manner similar to the one described in the synthesis of (1S,2S)-2-{4-[5-(3-tert-butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carbonyl}-cyclopentanecarboxylic acid above. HRMS m/z calcd for C29H37N3O4 [M+H]: 492.2857. Found: 492.2855.
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]=[CH2:14])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Li]CCCC.[F:26][C:27]1([F:38])[C:31]([F:32])=[C:30](F)[C:29]([F:35])([F:34])[C:28]1([F:37])[F:36]>CCOCC>[F:32][C:31]1[C:27]([F:26])([F:38])[C:28]([F:36])([F:37])[C:29]([F:34])([F:35])[C:30]=1[C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]=[CH2:14])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=Cc1ccc(-c2cc(Br)c(-c3ccccc3)s2)cc1
Reactant: FC1=C(F)C(F)(F)C(F)(F)C1(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Product: C=Cc1ccc(-c2cc(C3=C(F)C(F)(F)C(F)(F)C3(F)F)c(-c3ccccc3)s2)cc1
Temperature: -70 °C
Reaction time: 1.5 h
Yield: 67.1 %

Procedure:
Compound 31 (6.41 g, 18.8 mmol) was dissolved in 500 mL anhydrous Et2O and cooled to −25° C. n-BuLi (2.5 M in hexane, 9.8 mL, 24.4 mmol) was added dropwise over 45 min. Lithiation was determined to be complete by TLC after the addition of approximately 7 mL. The lithiated species precipitated from solution. Octafluorocyclopentene (5.18 mL, 37.6 mmol) was added and the reaction mixture stirred at −70° C. for 1.5 hours before warming slowly to −20° C. over 30 min, to 0° C. for 30 minutes then to room temperature for 1 hour. The reaction mixture was quenched with water and extracted with EtOAc (3×100 mL). The combined organic fractions were washed with brine, dried over MgSO4 and concentrated under vacuum. Purification by column chromatography afforded 32 (5.73 g, 67% yield). 1H NMR (600 MHz, CDCl3) δ 7.59 (d, J=8.3, 2H), 7.46 (d, J=8.2, 2H), 7.45-7.35 (m, 6H), 6.74 (dd, J=17.6, 10.9, 1H), 5.81 (d, J=17.6, 1H), 5.31 (d, J=10.9, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[N-:12]=[N+:13]=[N-:14].[Na+].[Cl-].[NH4+]>CN(C)C=O.O>[N:12]([C:3]1[C:2]([Br:1])=[CH:7][N:6]=[C:5]2[NH:8][CH:9]=[CH:10][C:4]=12)=[N+:13]=[N-:14]
Reactant: Clc1c(Br)cnc2[nH]ccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1c(Br)cnc2[nH]ccc12
Temperature: 110 °C
Yield: 43.1 %

Procedure:
5-Bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (1.5 g, 6.5 mmol), sodium azide (2.11 g, 32 mmol), and ammonium chloride (1.73 g, 32 mmol) were suspended in anhydrous dimethylformamide (10 mL). The reaction was heated to 110° C. for 19 h. The reaction mixture was diluted with water and the solids were collected. The solids were dissolved in a mixture of acetone and ethylacetate, the solution was filtered and concentrated to afford 4-Azido-5-bromo-1H-pyrrolo[2,3-b]pyridine (670 mg, 2.8 mmol, 43%). MS: m/z 238.0/240.0 (M+H+).
Reaction SMILES: [C:1]1(=[CH:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[N+:15]([O-])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[CH:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[NH2:15])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [H][H]
Reactant: COc1ccc(C=C2CCCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(CC2CCCC2)c(N)c1
Yield: 64.4 %

Procedure:
A solution of 1-(cyclopentylidenemethyl)-4-methoxy-2-nitrobenzene (1.8 g; 0.09 M, 7.72 mmol; 1 eq) in MeOH (80 mL) is pumped through the H-Cube™ flow hydrogenator fitted with a 10 mol % Pd/C catalyst cartridge (30×4 mm) heated to 25° C. at 1 bar with the full hydrogen option enabled. The flow rate is set at 1 mL/min. The catalyst is pre-saturated with hydrogen gas for 2 min before passing the substrate through. The solvent is evaporated under reduced pressure and the residue is taken up in HCl 1N and EtOAc. The organic phase is washed with brine then dried over MgSO4, and the solvent is evaporated under reduced pressure to afford 1.02 g (64%) of the title compound as a brown oil. 1H NMR (CDCl3) δ 6.94 (d, J=8.3 Hz, 1H), 6.45-6.35 (m, 2H), 4.45-3.90 (m, 2H), 3.75 (s, 3H), 2.45 (d, J=7.0 Hz, 2H), 2.12 (q, J=7.0 Hz, 1H), 1.78-1.45 (m, 6H), 1.35-1.05 (m, 2H). HPLC (max plot) 89%; Rt 2.86 min. LC/MS: (ES+): 206.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[CH:8](Cl)[CH3:9].[C:28]1(=[O:38])[NH:32][C:31](=[O:33])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]12.[K]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH2:15][C:14]([C:20]3[CH:21]=[C:22]([Cl:27])[CH:23]=[C:24]([Cl:26])[CH:25]=3)([C:16]([F:19])([F:17])[F:18])[O:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[CH:8]([N:32]1[C:31](=[O:33])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]2[C:28]1=[O:38])[CH3:9]
Reactant: CC(Cl)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 41.2 %

Procedure:
In a solution of 0.88 g of 3-[3-chloro-4-(1-chloroethyl)phenyl]-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole in 5 mL of N,N-dimethylformamide, 0.36 g of potassium phthalimide was added, and stirred at 100° C. for 1.5 hour. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, and diluted with 20 mL of ethyl acetate, washed with water (10 mL×3), and then dehydrated with and dried over saturated sodium chloride aqueous solution and anhydrous magnesium sulfate in that order, and the solvent was distilled off under reduced pressure. The residue was purified with medium pressure preparative liquid chromatography (medium pressure collection apparatus: YFLC-Wprep manufactured by Yamazen Corporation) that was eluted with ethyl acetate-hexane (gradient of 1:10 to 1:3) to obtain 0.45 g of the aimed product as pale yellow resinous substance.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[C:11]([OH:13])=O)[O:4][CH2:3][CH2:2]1.C[O-].[Na+].S(Cl)([Cl:19])=O>CO.C1(C)C=CC=CC=1>[O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[C:11]([Cl:19])=[O:13])[O:4][CH2:3][CH2:2]1
Reactant: O=C(O)C1CCCCC12OCCO2
Reactant: O=S(Cl)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(Cl)C1CCCCC12OCCO2
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1,4-dioxa-spiro[4.5]decane-6-carboxylic acid (2.42 g, 13 mmol) in methanol (6 mL) was added a 5.4 N solution of sodium methoxide in methanol (2.41 mL). The mixture was stirred at 20° C. for 20 min and the solvent was then evaporated under reduced pressure. Toluene (20 mL) was added to the residue and the solvent was evaporated under reduced pressure. The white solid obtained (2.5 g) was suspended in toluene (13 mL) and thionyl chloride (1 mL, 13.8 mmol) was added to the stirred solution at 20° C. over 10 min. Stirring was continued at 40° C. for 1 h when gas evolution stopped to give a ca 1 M solution of 1,4-dioxa-spiro[4.5]decane-6-carbonyl chloride in toluene.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])[O:9][CH2:8][CH2:7][O:6]1.[O:18]=[C:19]1[C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[N:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:21][NH:20]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:18]=[C:19]1[C:23]2([CH2:24][CH2:25][N:26]([CH2:2][CH2:3][CH2:4][C:5]3([C:10]4[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=4[F:17])[O:9][CH2:8][CH2:7][O:6]3)[CH2:27][CH2:28]2)[N:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:21][NH:20]1
Reactant: Fc1ccc(C2(CCCCl)OCCO2)c(F)c1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NCN(c2ccccc2)C12CCN(CCCC1(c3ccc(F)cc3F)OCCO1)CC2

Procedure:
A mixture of 4-chloro-1-(2,4-difluorophenyl)-1,1-ethylenedioxybutane (5.3 g), 4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]decane (4.6 g), anhydrous potassium carbonate (0.1 g) and dimethylformamide (58 ml) was heated under refluxing for 2.5 hours. After cooling, the reaction mixture was poured into cold water (400 ml) with vigorous stirring, and the precipitate was collected and washed with water to yield 4-(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]decan-8-yl)-1-(2,4-difluorophenyl)-1,1-ethylenedioxybutane. M.P. 58° - 62°C.
Reaction SMILES: [Br:1]Br.[CH3:3][S:4]([N:7]1[CH2:12][CH2:11][CH2:10][S:9][C:8]1=[CH:13][N+:14]([O-:16])=[O:15])(=[O:6])=[O:5].CCOCC>C(Cl)Cl>[CH3:3][S:4]([N:7]1[CH2:12][CH2:11][CH2:10][S:9][C:8]1=[C:13]([Br:1])[N+:14]([O-:16])=[O:15])(=[O:5])=[O:6]
Reactant: CS(=O)(=O)N1CCCSC1=C[N+](=O)[O-]
Reactant: BrBr
Solvent: ClCCl
Solvent: CCOCC
Product: CS(=O)(=O)N1CCCSC1=C(Br)[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
A solution of 1.6 g of bromine in 10 ml of methylene chloride was added drop-by-drop over a period of 10 minutes to a solution of 2.38 g of (1A) in 50 ml of methylene chloride at 0° C. and under a nitrogen blanket. The resulting mixture was stirred for a further 10 minutes, charcoaled, and stripped of solvent. The residue was dissolved in a minimum amount of methylene chloride, then ether was added to the solution, resulting in a gum. The gum was dissolved in methylene chloride, the solution was charged onto a flash chromatograph column (silica gel) and the product was eluted with methylene chloride, to give (1) on workup.
Reaction SMILES: [CH2:1]1[CH2:23][O:22][C:3]2([C:9]3[CH:10]=[CH:11][C:12]([CH:14]([CH3:17])[C:15]#[N:16])=[CH:13][C:8]=3[CH:7]=[CH:6][C:5]3[CH:18]=[CH:19][CH:20]=[CH:21][C:4]2=3)[O:2]1.[OH2:24].[OH-].[K+]>CO>[CH2:23]1[CH2:1][O:2][C:3]2([C:9]3[CH:10]=[CH:11][C:12]([CH:14]([CH3:17])[C:15]([NH2:16])=[O:24])=[CH:13][C:8]=3[CH:7]=[CH:6][C:5]3[CH:18]=[CH:19][CH:20]=[CH:21][C:4]2=3)[O:22]1
Reactant: O
Reactant: CC(C#N)c1ccc2c(c1)C=Cc1ccccc1C21OCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C(N)=O)c1ccc2c(c1)C=Cc1ccccc1C21OCCO1
Yield: 57 %

Procedure:
3.0 Gm. of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)propionitrile is refluxed for 3 hours in 50 ml. of water and 10 ml. of methanol containing 0.55 gm. of potassium hydroxide. The solution is cooled and extracted with ethyl acetate. The extract is washed with aqueous sodium carbonate and water, then dried and evaporated to yield 57% of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)propionamide. Use of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)acetonitrile and a 1 hour reaction time gives a similar yield of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)acetamide.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Cl.[P:13]([O:20]CC)([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]
Reactant: CCOP(OCC)OCC
Reactant: FC(F)(F)c1ccccc1CCl
Product: CCOP(=O)(Cc1ccccc1C(F)(F)F)OCC
Temperature: 160 °C

Procedure:
A mixture of 2-trifluoromethylbenzyl chloride (2.0 g, 10.0 mmol) and triethyl phosphite (2.13 g, 13 mmol) was heated at 160° C. under nitrogen for 3 hours. The excess triethyl phosphite was removed by distillation and the crude product obtained was distilled at 87°-90° C. (0.05 mm Hg) and isolated as a colorless oil; yield, 1.68 g, 56.8%; D.C.I.M.S.[MH+, 297].
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[N+:7]([O-])[CH:8]=[CH:9][CH:10]=1.P(Cl)(Cl)([Cl:18])=O>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Cl:18][C:8]1[N:7]=[CH:6][C:5]([O:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[F:1])=[CH:10][CH:9]=1
Reactant: [O-][n+]1cccc(Oc2ccccc2F)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Fc1ccccc1Oc1ccc(Cl)nc1

Procedure:
A solution of 25 g of 3-(o-fluorophenoxy)pyridine N-oxide in 50 ml of chloroform is added dropwise to 77 g of refluxing phosphorous oxychloride. The mixture is refluxed for 2 hours. The mixture is concentrated at reduced pressure. The oil is dissolved in 500 ml dichloromethane, washed with 50 ml of ice cold concentrated ammonium hydroxide and dried over anhydrous MgSO4. The organic phase is separated, concentrated at reduced pressure and distilled to yield the mixture of desired chlorinated pyridines as an oil, bp 92°-105° C. at 0.1 mm. The oil is dissolved in 50 ml of toluene and chromatographed over 450 g of silica gel in toluene to yield in the first eluate 6-chloro-3-(o-fluorophenoxy)pyridine. Continued elution with toluene yields 2-chloro-3-(o-fluorophenoxy)pyridine. Finally elution with toluene-methanol (50:50) yields 4-chloro-3-(o-fluorophenoxy)pyridine.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:22][O:21][C:20]3[CH:23]=[C:24]4[C:28](=[CH:29][C:19]1=3)[CH2:27][CH2:26][O:25]4)[C:5](=[O:18])[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1.CN(C)C1N=CC(B(O)O)=CC=1>>[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]2([CH2:22][O:21][C:20]4[CH:23]=[C:24]5[C:28](=[CH:29][C:19]2=4)[CH2:27][CH2:26][O:25]5)[C:5](=[O:18])[N:6]3[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:31]=1
Reactant: O=C1N(Cc2ccccn2)c2cccc(Br)c2C12COc1cc3c(cc12)CCO3
Reactant: OB(O)c1cccnc1
Agent: CN(C)c1ccc(B(O)O)cn1
Product: O=C1N(Cc2ccccn2)c2cccc(-c3cccnc3)c2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 4, and making non-critical variations using 4′-bromo-1′-(pyridin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 4′-bromo-1-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and pyridin-3-ylboronic acid to replace [6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound was obtained (9%) as a colorless solid: mp >200° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.52 (d, 1H), 8.42 (d, 1H), 7.96 (s, 1H), 7.79 (t, 1H), 7.40 (d, 1H), 7.29 (t, 2H), 7.18-7.08 (m, 2H), 7.00 (d, 1H), 6.81 (d, 1H), 6.72 (s, 1H), 5.98 (s, 1H), 5.08 (ABq, 2H), 4.56-4.40 (m, 4H), 3.10-2.90 (m, 2H); MS (ES+) m/z 448.5 (M+1).
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:13][N:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[CH2:19][CH2:20][NH2:21].[Na]>ClCCl>[CH3:13][N:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[CH2:19][CH2:20][NH:21][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: CN1CCCC1CCN
Agent: [Na]
Solvent: ClCCl
Product: CN1CCCC1CCNCc1cccc2ccccc12

Procedure:
Experimental condition analogous to Example 5, from 1-naphthalencarboxaldehyde 0.15 g (1 mmol), 2-(1-methyl-pyrrolidin-2-yl)-ethylamine 0.14 g (1.1 mmol), and sodium triacethoxyborohydride 0.31 g (1.5 mmol), in 10 mL dichloromethane. The crude material is 210 mg clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH3:12])[CH3:11])=[CH:4][CH:3]=1.C([O:17]O)(C)(C)C>ClCCl.O.[O-2].[Cr+3].[O-2].[O-2].[Cr+3]>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[C:6](=[O:17])[CH2:7][C:8]2([CH3:12])[CH3:11]
Reactant: CC1(C)CCc2ccc(Br)cc21
Reactant: CC(C)(C)OO
Agent: [Cr+3]
Agent: [O-2]
Solvent: ClCCl
Solvent: O
Product: CC1(C)CC(=O)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
6-Bromo-1,1-dimethyl-indan 8g (4 g, 17.8 mmol) was dissolved in 40 mL of anhydrous dichloromethane, followed by addition of chromium oxide (280 mg, 1.8 mmol) and slowly dropwise addition of tert-butyl hydroperoxide (19 mL, 190 mmol). The reaction system was sealed and stirred overnight at room temperature after the reaction solution was crimson and the generated gas was released. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was diluted with 50 mL of water and extracted with dichloromethane (100 mL×3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound 5-bromo-3,3-dimethyl-indan-1-one 19a (3.5 g, 82.3%) as a white solid.