Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]1[CH2:5][N:4]([C:6]2[N:11]=[CH:10][N:9]=[C:8]3[N:12]([CH3:16])[N:13]=[C:14](I)[C:7]=23)[CH2:3]1.[CH3:17][N:18]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[N:19]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][CH:2]1[CH2:5][N:4]([C:6]2[N:11]=[CH:10][N:9]=[C:8]3[N:12]([CH3:16])[N:13]=[C:14]([C:21]4[CH:20]=[N:19][N:18]([CH3:17])[CH:22]=4)[C:7]=23)[CH2:3]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cn1nc(I)c2c(N3CC(F)C3)ncnc21
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2nn(C)c3ncnc(N4CC(F)C4)c23)cn1
Reaction time: 1.5 h

Procedure:
4-(3-Fluoroazetidin-1-yl)-3-iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (C10) (500 mg, 1.50 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (910 mg, 2.63 mmol), tris(dibenzylideneacetone)dipalladium(0) (98%, 56 mg, 0.060 mmol), and tricyclohexylphosphine (96%, 35.1 mg, 0.120 mmol) were combined in 1,4-dioxane (10 mL). An aqueous solution of potassium phosphate (97%, 657 mg, 3.00 mmol) in water (5 mL) was added, and the reaction mixture was subjected to microwave irradiation at 150° C. and 200 W for 90 minutes. The reaction mixture was partitioned between ethyl acetate (20 mL) and aqueous phosphate buffer (20 mL), and the aqueous layer was extracted with ethyl acetate (2×20 mL) and dichloromethane (2×20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography [Gradient: 35% to 100% (10% methanol in ethyl acetate) in heptane] afforded the product as a glass. Yield: 302.3 mg, 1.05 mmol, 70%. LCMS m/z 288.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 3.83-3.92 (m, 2H), 3.93 (s, 6H), 4.14-4.26 (m, 2H), 5.23-5.43 (m, 1H, JHF=58.0 Hz), 7.63 (d, J=0.6 Hz, 1H), 7.99 (br s, 1H), 8.35 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:12][C:13]([NH:15][NH2:16])=O)[CH:8]=2)[N:3]=1.Cl[C:18]1[N:19]=[N:20][C:21]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:22][CH:23]=1>C(O)CCC>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:12][C:13]3[N:19]4[N:20]=[C:21]([C:24]5[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=5)[CH:22]=[CH:23][C:18]4=[N:16][N:15]=3)[CH:8]=2)[N:3]=1
Reactant: Clc1ccc(-c2cccnc2)nn1
Reactant: NNC(=O)Cc1ccc2nc(Cl)ccc2c1
Solvent: CCCCO
Product: Clc1ccc2cc(Cc3nnc4ccc(-c5cccnc5)nn34)ccc2n1
Temperature: 25 °C
Yield: 35.9 %

Procedure:
(2-Chloro-quinolin-6-yl)-acetic acid hydrazide (0.030 g, 0.127 mmol) and 3-chloro-6-pyridin-3-yl-pyridazine (0.024 g, 0.127 mmol) were heated to reflux in butanol (0.5 mL) for several hours. The reaction was cooled to room temperature and filtered. The filtrate was purified via reverse phase HPLC on a C18 column eluting with acetonitrile in water (0.1% TFA) to give 0.017 g (35%) of 2-chloro-6-(6-pyridin-3-yl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-quinoline. 1H NMR (400 MHz, CD3OD) δ 9.38 (m, 1H), 8.88 (d, 1H, J=5.2 Hz), 8.85 (m, 1H), 8.42 (d, 1H, J=9.6 Hz), 8.31 (d, 1H, J=8.8 Hz), 8.06 (s, 1H), 8.03 (m, 1H), 7.92 (m, 3H), 7.50 (d, 1H, J=8.8 Hz), 4.93 (s, 2H). Mass spectrum (LCMS, ESI pos.): Calcd for C20H13ClN6; found: 373.3, 375.3 (M+H).
Reaction SMILES: Cl[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[NH:17]1[CH2:19][CH2:18]1>CCOC(C)=O>[N:17]1([C:2]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=2[N+:14]([O-:16])=[O:15])[CH2:19][CH2:18]1
Reactant: C1CN1
Reactant: NC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Product: NC(=O)c1cc([N+](=O)[O-])c(N2CC2)c([N+](=O)[O-])c1

Procedure:
Reaction of 4-chloro-3,5-dinitrobenzamide (Ullman et al., Annalen, 1909, 366, 82) with aziridine in EtOAc as above for 2 h gave 19: mp 228-231° C., 1H NMR [(CD3)2SO] δ8.68 (s, 2H, H-2,6), 8.33, 7.75 (2 br s, 2H, CONH2), 2.36 (s, 4H, aziridine-H), 13NMR 163.77 (s), 145 16 (s), 143.40 (s), 128.43 (d), 125.89 (s), 30 61 (t). Anal. Calcd for C9H8N4O5: C, 42.86;H, 3.20, N, 22.22. Found: C, 43.15,H, 2.98; N, 22.13%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[CH2:21][CH2:22][OH:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[CH2:21][CH2:22][O:23][S:30]([C:27]1[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=1)(=[O:32])=[O:31])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(CCO)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC2CN(C(=O)OC(C)(C)C)CCN2C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A solution of 1,4-di(tert-butoxycarbonyl)-2-(2-hydroxyethyl)piperazine (5.05 g) and p-toluenesulfonyl chloride (4.34 g) in methylene chloride (200 ml) was cooled to 0° C., followed by the dropwise addition of triethylamine (11 ml). The resulting mixture was stirred at 0° C. for 1 hour and at room temperature for 1 day. The reaction mixture was concentrated under reduced pressure. After dilution with ethyl acetate, the residue was washed with 1N hydrochloric acid, water and saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate/hexane=1/4 to 1/1) using, as a carrier, silica gel, whereby the title compound (4.82 g) was obtained as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=[O:5]>[Pd]>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1c(F)cccc1F
Agent: [Pd]
Product: OCc1c(F)cccc1F
Temperature: 80 °C
Yield: 85.5 %

Procedure:
332 g of 2,6-difluorobenzaldehyde were placed under nitrogen in a 0.7 1 autoclave and admixed with 6.4 g of 5% strength by weight palladium-on-carbon (catalyst from Heraeus type K-0227, containing 50% by weight of water). The autoclave was closed and purged with nitrogen. 50 bar of hydrogen were then injected and the contents of the autoclave were heated to 80° C. Hydrogenation was carried out for a total of 4 hours while stirring. After cooling and venting, the reaction mixture was filtered through Celite® filter aid, the autoclave was rinsed with 50 g of isopropanol and the filter cake was washed with 150 g of isopropanol. The solvent was distilled from the combined filtrates and washings and the crude product mixture was subsequently distilled off. 288 g of 2,6-difluorobenzyl alcohol were obtained (90% of theory).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[OH:9][C@H:10]([CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:11][NH:12][C@H:13]([CH3:22])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1>CS(C)=O>[OH:9][C@H:10]([CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:11][NH:12][C@H:13]([CH3:22])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])=[CH:17][CH:16]=1
Reactant: OCCCCCCCl
Reactant: C[C@H](Cc1ccc(O)cc1)NC[C@H](O)COc1ccccc1
Solvent: CS(C)=O
Product: C[C@H](Cc1ccc(OCCCCCCO)cc1)NC[C@H](O)COc1ccccc1
Reaction time: 1 h

Procedure:
300 ml of 6-chlorohexanol were added to a solution of 602 mg of p-[(R)-2-[[(S)-2-hydroxy-3-phenoxypropyl]-amino]propyl]phenol and 246 mg of potassium t-butylate in 10 ml of dimethylsulfoxide and the reaction mixture was stirred at 80° for 1 hour. The reaction mixture was evaporated in a high vacuum and the residue was chromatographed on silica gel with chloroform/n-propanol/saturated ammonia (1000:50:3), whereby there were obtained 500 mg of pure, amorphous 6-[p-[(R)-2-[[(S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenoxy]hexanol, [α]D20 =-21° (c=0.9 in methanol), ε222 =17230.
Reaction SMILES: C([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[C:26]([CH:27]=[O:28])=[C:25]([Cl:29])[N:24]=[C:23]3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:17]([Cl:36])[CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[Cl:36][C:17]1[CH:16]=[C:15]([C:10]2[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:20]=[CH:19][C:18]=1[CH2:21][N:22]1[C:26]([CH:27]=[O:28])=[C:25]([Cl:29])[N:24]=[C:23]1[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(Cn2c(-c3ccccc3)nc(Cl)c2C=O)c(Cl)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccccc1-c1ccc(Cn2c(-c3ccccc3)nc(Cl)c2C=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 111.5 %

Procedure:
1.5 g of 3′-chloro-4′-(4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl)-biphenyl-2-sulfonic acid tert-butylamide and 340 μl of anisole are dissolved in 10 ml of trifluoroacetic acid and the solution is stirred at RT for 24 h. The volatile constituents are removed in vacuo, the residue is taken up twice using 50 ml of toluene each time and the volatile constituents are again removed in vacuo. 1.5 g of a colorless foam are obtained.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1.[CH3:13][O:14][C:15](=[O:38])[CH2:16][CH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:28]=[CH:27][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][CH:24]=2)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>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.COCCOC>[CH3:13][O:14][C:15](=[O:38])[CH2:16][CH:17]1[CH2:18][CH2:19][CH:20]([C:23]2[CH:24]=[CH:25][C:26]([C:2]3[C:7]([O:8][CH3:9])=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=3)=[CH:27][CH:28]=2)[CH2:21][CH2:22]1
Reactant: COC(=O)CC1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: COc1cc([N+](=O)[O-])cnc1Cl
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: [K+]
Solvent: COCCOC
Product: COC(=O)CC1CCC(c2ccc(-c3ncc([N+](=O)[O-])cc3OC)cc2)CC1
Temperature: 100 °C

Procedure:
To a solution of 2-chloro-3-methoxy-5-nitro-pyridine (0.10 g, 0.53 mmol, 1.0 equiv) and {4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (0.2 g, 0.56 mmol, 1.05 equiv) in 5 Ml DME was added 0.5 Ml saturated potassium carbonate solution and 10 mg Pd(PPh3)4 catalyst. The reaction was heated to 100° C. for 2 h. The crude reaction mixture was then concentrated in vacuo and then loaded directly onto a silica gel column. Elution with 30% EtOAc/hexanes afforded the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12-1.19 (m, 2H) 1.15 (d, J=13.14 Hz, 1H) 1.46-1.59 (m, 1H) 1.51 (dd, J=112.38, 2.78 Hz, 2H) 1.81 (d, J=5.56 Hz, 4H) 2.26 (d, J=6.82 Hz, 2H) 3.61 (s, 3H) 4.00 (s, 3H) 7.36 (d, J=8.34 Hz, 2H) 7.90 (d, J=8.34 Hz, 2H) 8.20 (d, J=2.02 Hz, 1H) 9.05 (s, 1H); (M+H)+385.1.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:12])[CH:9]([CH3:11])[CH3:10].[NH2:14][C:15]1[NH:16][CH:17]=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[C:19]=1[C:20]([NH2:22])=[O:21]>O1CCCC1.O>[C:8]([NH:14][C:15]1[NH:16][CH:17]=[C:18]([C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)[C:19]=1[C:20]([NH2:22])=[O:21])(=[O:12])[CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)C(=O)Cl
Reactant: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)c[nH]c1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)C(=O)Nc1[nH]cc(-c2ccc([N+](=O)[O-])cc2)c1C(N)=O
Reaction time: 16 h
Yield: 119 %

Procedure:
0.260 cm3 (1.86 mmol) of triethylamine and 0.098 cm3 (0.93 mmol) of isobutyryl chloride are added, at a temperature close to 25° C., to a solution of 0.23 g (0.93 mmol) of 2-amino-4-(4-nitrophenyl)-1H-pyrrole-3-carboxamide in 15 cm3 of tetrahydrofuran. After stirring for 16 hours at this temperature, the reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is stirred in 60 cm3 of water and then extracted with twice 50 cm3 of ethyl acetate. The organic phase is dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 0.35 g of 2-isobutyrylamino-4-(4-nitro-phenyl)-1H-pyrrole-3-carboxamide in the form of a green powder. 1H NMR (400 MHz, (CD3)2SO, —δ in ppm) 15 (d, J=7.0 Hz, 6H); 2.64 (m, 1H); from 6.50 to 8.50 (very broad m, 2H); 6.79 (d, J=2.5 Hz, 1H); 7.64 (d, J=9.0 Hz, 2H); 8.19 (d, J=9.0 Hz, 2H); 10.45 (broad s, 1H); 11.65 (broad s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:6]=2[CH:22]=1.[CH2:23]=[O:24]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH2:23][OH:24])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:6]=2[CH:22]=1
Reactant: C=O
Reactant: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccn1)=NC2
Solvent: Cc1ccccc1C
Product: OCCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccn1)=NC2

Procedure:
In the manner given in Example 1, 8-chloro-methyl-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in xylene is heated in an oil bath with repeated additions of portions of paraformaldehyde to give 8-chloro-1-(2-hydroxyethyl)-6-(2-pyridyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:14]1[CH2:29][CH2:28][N:17]2[C:18]3[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=3[NH:20][C:21](=O)[CH2:22][CH:16]2[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[CH2:7]([N:14]1[CH2:29][CH2:28][N:17]2[C:18]3[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=3[NH:20][CH2:21][CH2:22][CH:16]2[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1CC2CN(Cc3ccccc3)CCN2c2ccccc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(CN2CCN3c4ccccc4NCCC3C2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Solid LiAlH4 (180 mg, 4.74 mmol) was added at room temperature to a stirring solution of the product of Example 26C (280 mg, 0.911 mmol) in tetrahydrofuran (10 mL). The resulting mixture was stirred at room temperature under nitrogen for 12 hours, then heated at 60° C. for 1 hour. The reaction mixture was cooled in ice and quenched by successive addition of ethyl acetate (4 mL), water (0.18 mL), 15% NaOH (0.18 mL) and water (0.54 mL). The mixture was filtered through diatomaceous earth with an ethyl acetate (25 mL) rinse. The filtrate was concentrated and the residue was purified by preparative HPLC (30×100 mm, C18, Waters XBridge™ column eluted with 0.1 M (NH4)2CO3(aq)-methanol (95:5-10:90) over 18 minutes) to provide the title compound: 1H NMR (400 MHz, CD3OD) δ ppm 1.53-1.63 (m, 1H), 1.94-2.06 (tddd, J=12.0, 12.0, 6.1, 3.2, 3.1 Hz, 1H), 2.29 (t, J=10.4 Hz, 1H), 2.37 (td, J=10.8, 3.1 Hz, 1H), 2.63 (ddd, J=10.5, 2.6, 2.2 Hz, 1H), 2.85 (dq, J=11.0, 2.7 Hz, 1H), 2.90-3.01 (m, 2H), 3.09 (ddd, J=12.2, 5.2, 2.7 Hz, 1H), 3.21 (td, J=11.1, 2.9 Hz, 1H), 3.53 (td, J=12.1, 1.5 Hz, 1H), 3.58 (s, 2H), 6.62 (dd, J=7.6, 1.5 Hz, 1H), 6.73 (td, J=7.6, 1.7 Hz, 1H), 6.80 (td, J=7.6, 1.7 Hz, 1H), 6.89 (dd, J=7.9, 1.5 Hz, 1H), 7.23-7.29 (m, 1H), 7.29-7.39 (m, 4H); MS (ESI) m/z 294 (M+H)+.
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]2)O[CH2:2]1.C([O:14][C:15]1[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=1)C>>[CH2:1]([O:11][C:4]1[CH:5]=[CH:6][C:7]([CH:18]2[CH2:19][CH2:20][C:15](=[O:14])[CH2:16][CH2:17]2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CCOc1ccc(Br)cc1
Product: CCOc1ccc(C2CCC(=O)CC2)cc1

Procedure:
Cyclohexane-1,4-dione monoethyleneacetal is reacted with a Grignard reagent prepared from 1-ethoxy-4-bromobenzene, and the product is dehydrated and then hydrogenated in the same manner as in process A (if desired, ethyleneacetal is re-introduced). The acetal moiety is removed to obtain 4-(4-ethoxyphenyl)cyclohexanone, which is then deuterated in the same manner as in process A to obtain 4-(4-ethoxyphenyl)cyclohexanone-2,2,6,6-d4. The deuterated compound is reacted with a Grignard reagent prepared from propyl bromide, and the product is dehydrated and hydrogenated. The cis-compound is separated to obtain 1-(trans-4-propylcyclohexyl-3,3,5-d3)-4-ethoxybenzene. ##STR61##
Reaction SMILES: [Cl:1][C:2](Cl)([F:10])[C:3]([F:9])([F:8])[C:4]([Cl:7])([F:6])[F:5].C(O)(C)C>>[Cl:7][C:4]([C:3]([CH:2]([F:10])[Cl:1])([F:9])[F:8])([F:6])[F:5]
Reactant: FC(F)(Cl)C(F)(F)C(F)(Cl)Cl
Solvent: CC(C)O
Product: FC(Cl)C(F)(F)C(F)(F)Cl
Temperature: 0 °C
Yield: 55.3 %

Procedure:
1,1,3-trichloro-1,2,2,3,3-pentafluoropropane(produced in Part C above) (106.6 g, 0.45 mol) and 300 g(5 mol) isopropanol were stirred under an inert atmosphere and irradiated 4.5 hours with a 450 W Hanovia Hg lamp at a distance of 2-3 inches(5-7.6 cm). The acidic reaction mixture was then poured into 1.5 liters ice water. The organic layer was separated, washed twice with 50 ml water, dried with calcium sulfate, and distilled to give 50.5 g ClCF2CF2CHClF, bp 54.5°-56° C. (55%). 1H NMR (CDCl3): ddd centered at 6.43 ppm. J H--C--F=47 Hz, J H--C--C--Fa=12 Hz, J H--C--C--Fb=2 Hz.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl.[F:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21].FC1C(C)=CC([CH:27]=[O:28])=CC=1C>Cl>[F:13][C:14]1[C:19]([CH3:20])=[C:18]([CH:17]=[CH:16][C:15]=1[CH3:21])[CH:27]=[O:28]
Reactant: Cc1cc(C=O)cc(C)c1F
Reactant: Cc1cccc(C)c1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: Cc1ccc(C=O)c(C)c1F
Temperature: 50 °C
Yield: 68.6 %

Procedure:
62.4 g of aluminum chloride (mol. Wt. 133.34; 468.0 mmol), 450.0 g of 1,2-dichlorobenzene (mol. Wt. 147.00; 3,061 mmol), and about 48.00 g of 2-fluoro-m-xylene (mol. Wt. 124.16; 386.6 mmol) were charged to a 2 liter Parr®-brand 4522 stainless steel reaction vessel. To this mixture was added 5 drops of concentrated HCl. The vessel was sealed, heated to 50° C., and purged three times with carbon monoxide with the pressure of the vessel increased to 100 psi for each purging. After the third purge, the vessel was vented and a final introduction of CO was made at a pressure of about 200 psi, the pressure at which the reaction was maintained for the total reaction time of about 16 hours (the reaction temperature was maintained at 50° C. for the duration as well). Once the reaction was complete, the resultant mixture (exhibiting a dark orange color) was poured into about 500 mL of ice water (which turned the solution a yellow color), to which was added 500 mL of cyclohexane. The top, organic layer was removed and washed three times with water using a separatory funnel and dried over magnesium sulfate. The residual organic phase was then distilled under vacuum to remove excess cyclohexane, 2-fluoro-m-xylene, 1,2-dichlorobenzene, and left about 40.39 g of a benzaldehyde mixture consisting of 4-fluoro-3,5-dimethylbenzaldehyde (73.8%) and 3-fluoro-2,4-dimethylbenzaldehyde (26.2%) (mol. Wt. 152.17; 265.4 mmol; yield of approximately 68.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:10][CH2:9][C:3]1[CH:4]=[C:5]([I:8])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(I)ccc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(I)cc1CBr
Yield: 55 %

Procedure:
A mixture of 2-chloro-5-iodo-toluene (0.5 g, 1.98 mmol), N-bromosuccinimide (0.422 g, 2.35 mmol) and benzoyl peroxide (21.5 mg, 0.089 mmol) in dry CCl4 (5 mL) was stirred and heated to reflux for 3 h. After cooling, the mixture-was filtered, and the red filtrate was washed with a saturated solution of sodium thiosulfate (2×10 mL). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (petroleum ether), to give 60 as a white solid (361 mg, 55%). 1H NMR (CDCl3, 300 MHz) δ 7.76 (d, J=2.4 Hz, 1H), 7.56 (dd, J=8.7, 2.1 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 4.49 (s, 2H). MS (m/e) (positive FAB) 332.1 (M+H)+, m.p. 94-95° C.
Reaction SMILES: [CH:1]1[C:9]([NH2:10])=[CH:8][C:7]2[CH2:11][CH2:12][N:5]3[C:6]=2[C:2]=1[C:3]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:4]=13.[C:19](Cl)(=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>ClCCl>[CH:1]1[C:9]([NH:10][C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:8][C:7]2[CH2:11][CH2:12][N:5]3[C:6]=2[C:2]=1[C:3]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:4]=13
Reactant: CCCCCC(=O)Cl
Reactant: Nc1cc2c3c(c1)c1c(n3CC2)CCCCCC1
Solvent: ClCCl
Product: CCCCCC(=O)Nc1cc2c3c(c1)c1c(n3CC2)CCCCCC1
Yield: 36.1 %

Procedure:
Following the procedure of Example 1, Step 4, 4,5,7,8,9,10,11,12-octahydrocycloocta[b]pyrrolo[3,2,1-hi]indol-2-amine (0.15 g, 0.54 mmol), hexanoyl chloride (0.075 mL, 0.54 mmol) and poly-(4-vinylpyridine) (500 mg) in dichloromethane (12 mL) provided N-4,5,7,8,9,10,11,12-octahydrocycloocta[b]pyrrolo[3,2,1-hi]indol-2-ylhexanamide (66 mg). MS (ES) m/z 339.2; HPLC purity 100% at 210-370 nm, 11.2 min.; 100% at 250 nm, 11.2 min. (Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 ((Ammon. Form. Buff. pH=3.5/ACN and MeOH) for 10 min, hold 4 min); HRMS: calcd for C22H30N2O+H+, 339.24309; found (ESI, [M+H]+), 339.2433.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([S:15]([C:18]3[C:19]([CH3:24])=[CH:20][CH:21]=[CH:22][CH:23]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)O1.[CH3:26][O:27][C:28](=[O:50])[CH2:29][C:30]1[C:39]([CH3:40])=[C:38](OS(C(F)(F)F)(=O)=O)[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([F:49])[CH:36]=2)[CH:31]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[Cl-].[Na+].O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH3:26][O:27][C:28](=[O:50])[CH2:29][C:30]1[C:39]([CH3:40])=[C:38]([C:9]2[CH:10]=[CH:11][C:12]([S:15]([C:18]3[C:19]([CH3:24])=[CH:20][CH:21]=[CH:22][CH:23]=3)(=[O:16])=[O:17])=[CH:13][CH:14]=2)[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([F:49])[CH:36]=2)[CH:31]=1
Reactant: Cc1ccccc1S(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(OS(=O)(=O)C(F)(F)F)c1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)c3ccccc3C)cc2)c1C
Temperature: 125 °C
Yield: 30.9 %

Procedure:
To a mixture of 4,4,5,5-tetramethyl-2-[4-(toluene-2-sulfonyl)-phenyl]-[1,3,2]dioxaborolane (50 mg, 0.14 mmol), (6-fluoro-3-methyl-4-trifluoromethanesulfonyloxy-naphthalen-2-yl)-acetic acid methyl ester (73 mg, 0.19 mmol), K3PO4 (81 mg, 0.38 mmol), palladium(II) acetate (14 mg, 0.06 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (49 mg, 0.12 mmol) were added anhydrous toluene (4 mL) and water (400 uL) at room temperature. The resulting light brown solution was heated to 125° C. for 15 hours. The reaction mixture was cooled to room temperature and diluted with brine solution and ethyl acetate. The two layers were separated and the aqueous layer was extracted with ethyl acetate and the combined extracts were washed with brine solution. The organic layer was dried over anhydrous MgSO4. Filtration and concentration gave a crude residue which was purified using an ISCO (40 g) column, eluting with 0-40% ethyl acetate in hexanes, to give {6-fluoro-3-methyl-4-[4-(toluene-2-sulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (20 mg, 31%). 1H NMR (300 MHz, CDCl3) δ ppm 8.31 (d, J=7.5 Hz, 1 H), 8.01 (d, J=7.8 Hz, 2 H), 7.80 (dd, J=8.5, 6.0 Hz, 1 H), 7.75 (s, 1 H), 7.50-7.62 (m, 1 H), 7.47 (d, J=7.5 Hz, 1 H), 7.40 (d, J=7.8 Hz, 2 H), 7.32 (d, J=7.2 Hz, 1 H), 7.19 (td, J=8.5, 2.0 Hz, 1 H), 6.72 (d, J=10.9 Hz, 1 H), 3.85 (s, 2 H), 3.73 (s, 3 H), 2.56 (s, 3 H), 2.09 (s, 3 H). HRMS calcd. for C27H24FO4S [(M+H)+] 463.1374, obsd. 463.1373.