Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][C:4](Br)=[CH:3][CH:2]=1.[Br-].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1.CC(C)([O-])C.[Na+].C1(C(C2C=CC=CC=2)=C(P(C2CCCCC2)C2CCCCC2)C)C=CC=CC=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:4]2[CH:5]=[CH:6][C:1]([CH3:8])=[CH:2][CH:3]=2)=[CH:14][CH:13]=1
Reactant: COc1ccc(N)cc1
Reactant: Cc1ccc(Br)cc1
Agent: CC(=C(c1ccccc1)c1ccccc1)P(C1CCCCC1)C1CCCCC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Product: COc1ccc(Nc2ccc(C)cc2)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 88.9 %

Procedure:
Into a reactor were introduced 0.330 g (1.93 mmol) of p-tolyl bromide and 4 mL of toluene under a nitrogen atmosphere. The bromide was dissolved in the solvent. To this solution were added 0.266 g (2.16 mmol) of p-anisidine, 0.226 g (2.35 mmol) of sodium t-butoxide, 8.5 mg (1 mol % based on the amine) of tris(dibenzylidene)dipalladium, and 32.3 mg (2 mmol % based on the amine) of the 1,1-diphenyl-2-(dicyclohexylphosphino)propene obtained in Example 2. The resultant reaction mixture was stirred at 100° C. for 5 hours and then cooled. Saturated aqueous ammonium chloride solution was added thereto, and this mixture was extracted with toluene. The extract was dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The concentrate was purified by column chromatography to obtain 0.366 g (89%) of N-p-methoxyphenyl-N-p-tolylamine. The results obtained are shown in Table 20.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:16]2[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=NC(OC)=CC=2)CCCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:25]1([CH2:24][N:15]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:31])=[O:3])=[CH:8][N:9]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCCC2)c2ccc(OC)nc2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: COc1ccc(NCC2CCCCC2)cn1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Product: COc1ccc(N(CC2CCCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)cn1

Procedure:
The title compound was prepared via {2-[3-cyclohexylmethyl-3-(6-methoxy-pyridin-3-yl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclohexylmethyl-(6-methoxy-pyridin-3-yl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12].C([Li])CCC.C([O:21][B:22](OCC)[O:23]CC)C>C1COCC1>[CH2:9]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:22]([OH:23])[OH:21])[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: CCOB(OCC)OCC
Reactant: CC(C)CCOc1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)CCOc1ccccc1B(O)O
Temperature: -78 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
To a solution of 1-bromo-2-(isopentyloxy)benzene (9.68 g, 40 mmol) in THF (160 mL) was added dropwise n-butyl lithium (1.6 M in hexanes, 1.05 eq., 26.3 mL) under nitrogen at −78° C. over 30 min. After further stirring for 1 hour at −78° C., triethylborate (5.86 mL, 51.3 mmol) was added. The cooling bath was removed and the reaction mixture was stirred overnight at rt. An aqueous solution of 2 N HCl (20 mL) was added and the reaction solution stirred for 30 min, at which point 50 mL of water was added. The reaction mixture was extracted with ether (5×80 mL), dried over anhydrous sodium sulfate, filtrated and concentrated to yield 2-(isopentyloxy)phenylboronic acid (6.30 g, 77% yield). 1H NMR (400 MHz, CDCl3): 7.83 (d, 1H), 7.43 (dd, 1H), 7.03 (t, 1H), 6.93 (d, 1H), 6.05 (s, 2H), 4.10 (t, 2H), 1.86-1.75 (m, 3H), 1.0 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH:6]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:5]2.[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(N1C2C(=CC(C3C=CC=CC=3)=CC=2)C[C@H](NS(C2C=CC=CC=2)(=O)=O)C1)C1C=CC=CC=1>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][CH2:7][CH:6]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:5]3)=[CH:25][CH:24]=1
Reactant: O=S(=O)(NC1CNc2ccc(Br)cc2C1)c1ccccc1
Reactant: OB(O)c1ccc(F)cc1
Agent: O=S(=O)(N[C@H]1Cc2cc(-c3ccccc3)ccc2N(Cc2ccccc2)C1)c1ccccc1
Product: O=S(=O)(NC1CNc2ccc(-c3ccc(F)cc3)cc2C1)c1ccccc1

Procedure:
Compound 113A was prepared from 87A and 4-fluorophenylboronic acid by procedures analogous to those described in 89E.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([NH2:13])[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[O:14]=[C:15]1[CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH2:18][CH2:17][N:16]1[CH2:27][C:28](O)=[O:29].C(N=C=NCCCN(C)C)C>ClCCl>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([NH:13][C:28](=[O:29])[CH2:27][N:16]3[CH2:17][CH2:18][CH2:19][CH:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:15]3=[O:14])[CH2:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: NC1(c2ccc(F)cc2)CCC1
Reactant: O=C(O)CN1CCCC(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)C1=O)NC1(c2ccc(F)cc2)CCC1
Reaction time: 60 h

Procedure:
To a solution of 1-(4-fluorophenyl)cyclobutanamine hydrochloride (0.048 g, 0.236 mmol) and 2-(2-oxo-3-phenylpiperidin-1-yl)acetic acid (Example 91D, 0.050 g, 0.214 mmol) in dichloromethane (0.5 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.049 mL, 0.279 mmol) (0.049 mL, 0.279 mmol), and the reaction was stirred for approximately 60 hours. The reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute). The product was dissolved in a minimal ethyl acetate and hexanes was added which caused the product to precipitate from solution. Concentration gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.34-7.43 (m, 2H), 7.22-7.34 (m, 3H), 7.14-7.20 (m, 2H), 7.09-7.11 (br s, 1H), 6.97-7.03 (m, 2H), 4.03 (d, J=14.1 Hz, 1H), 3.87 (d, J=14.1 Hz, 1H), 3.69 (dd, J=7.9, 6.0 Hz, 1H), 3.51-3.60 (m, 1H), 3.39-3.48 (m, 1H), 2.47-2.60 (m, 4H), 1.78-2.17 (m, 6H); MS (ESI−) m/z 379 (M−H)−.
Reaction SMILES: [C-]#[C-].[Li+].[Li+].[CH2:5](N)[CH2:6]N.[C:9]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[NH4+].[Cl-]>C1COCC1>[C:5]([C:9]1([OH:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)#[CH:6]
Reactant: O=C1CCCCCCC1
Reactant: NCCN
Agent: [C-]#[C-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C#CC1(O)CCCCCCC1
Temperature: 45 °C
Reaction time: 15 h
Yield: 106.7 %

Procedure:
At 35° C., a solution of lithium acetylide-ethylene diamine (50 g, 0.49 mol) in THF (500 ml) was slowly treated (reaction temperature≦35° C.) with a solution of cyclooctanone (51.4 g, 0.41 mol) in THF (100 ml). The resulting mixture was stirred for 4 h at 20° C., 15 h at 45° C., cooled to 5° C., treated with aqueous sat. NH4Cl solution (250 ml) and washed with 3M aqueous HCl. After extraction with Et2O, the organic phases were washed with water, aqueous sat. Na2CO3 solution, dried (Na2SO4), and concentrated to give 1-ethynylcyclooctanol (66.6 g). A solution of crude 1-ethynylcyclooctanol (65 g) in formic acid (130 ml) was heated for 2.5 h at 80° C. The resulting mixture was taken up in Et2O and washed successively with water, 5M NaOH, water, aqueous sat. NH4Cl solution, dried (Na2SO4), and concentrated to give 56 g of crude product. A fraction (8 g) was purified by flash chromatography (hexane/Et2O 95:5→9:1) to give 4.1 g of 1-cyclooct-2-enylethanone.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([NH:8][S:9]([NH:12]C(OCC1C=CC=CC=1)=O)(=[O:11])=[O:10])[CH2:5][CH2:6][CH3:7]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:23])[CH:4]([NH:8][S:9]([NH2:12])(=[O:10])=[O:11])[CH2:5][CH2:6][CH3:7]
Reactant: CCCC(NS(=O)(=O)NC(=O)OCc1ccccc1)C(=O)OC
Agent: [Pd]
Solvent: CO
Product: CCCC(NS(N)(=O)=O)C(=O)OC
Reaction time: 2 h
Yield: 67 %

Procedure:
A solution of 2-(N-carbobenzyloxyaminosulfonyl)aminopentanoic acid methyl ester (33 g) in methanol (250 ml) under nitrogen was cooled to 0° C. and 1.4 g of 10% Pd/C was added. The mixture was placed into a Parr Apparatus and hydrogenated at 55 psi for 2 hours. The catalyst was removed on a pad of CELITE® and the filtrate was concentrated in vacuo and purified by flash silica gel chromatography (50% ethyl acetate in hexane) to afford 13.5 g (76%) of 2-(amino sulfonyl)aminopentanoic acid methyl ester (Formula VII: R=CH3 ; R1 =H; R2 =propyl; R3 =H) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:15](=O)[C:16]([F:19])([F:18])[F:17])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C[Si]([N-:25][Si](C)(C)C)(C)C.[Li+].CSC.B.[OH-].[Na+]>C1(C)C=CC=CC=1>[NH2:25][CH:15]([C:13]1[CH:12]=[C:4]([CH:3]=[C:2]([Br:1])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[C:16]([F:19])([F:18])[F:17]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(C(=O)C(F)(F)F)c1
Agent: B
Agent: [Li+]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CSC
Product: CC(C)(C)OC(=O)c1cc(Br)cc(C(N)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.2 %

Procedure:
To a solution of tert-butyl 3-bromo-5-(trifluoroacetyl)benzoate (3.0 g, 8.5 mmol) in toluene (mL) was slowly added lithium bis(trimethylsilyl)amide (1.0 M in toluene; 25.5 mL, 25.5 mmol). The reaction was stirred at ambient temperature. After 1 h, the reaction was checked by TLC for disappearance of tert-butyl 3-bromo-5-(trifluoroacetyl)benzoate. Borane dimethyl sulfide complex (2.0 M in toluene; 25.5 mL, 51.0 mmol) was added and the mixture was stirred at ambient temperature. After 1 h, aqueous NaOH (1.0 M) was added slowly to quench the reaction. The mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→70% hexanes/ethyl acetate) gave the title compound (1.48 g).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH:6]([CH:10]([C:15]([O:17][CH3:18])=[O:16])[C:11]([O:13][CH3:14])=[O:12])[CH2:5]1.[H][H].O>CN(C)C=O>[CH2:7]([C:10]([CH:6]1[CH2:7][CH2:8][CH2:9][CH:4]([CH3:3])[CH2:5]1)([C:11]([O:13][CH3:14])=[O:12])[C:15]([O:17][CH3:18])=[O:16])[CH2:8][CH2:9][CH2:4][CH:5]=[CH2:6]
Reactant: [H][H]
Reactant: COC(=O)C(C(=O)OC)C1CCCC(C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCCCCC(C(=O)OC)(C(=O)OC)C1CCCC(C)C1

Procedure:
To a slurry of sodium hydride (2.53 g, 0.06 mol) in anhydrous N,N-dimethylformamide (50 mL) was added dropwise dimethyl 2-(3-methylcyclohexyl)-malonate (14.46 g, 0.06 mol). After complete addition, the reaction was stirred until no more hydrogen gas was evolved. To the reaction was then added dropwise 1-bromo-6-hexene (10.33 g, 0.06 mol) followed by stirring. The progress of the reaction was followed by analytical chromatography using silica plates and ethyl acetate:hexanes (40:60). After complete reaction, water (20 mL) was added and most of the solvents removed under high vacuum. The remaining material was partitioned between water and ether and the ether layer washed twice with water. The ether solution was dried with MgSO4 and evaporated to give a thick yellow oil. The product was then distilled at 127-134° C. and 0.4 mm pressure to give clear oil.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10](O)[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@:20]([CH3:21])([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.ClC(OC)=O.N1C=CC=CC=1.CO.C(=O)([O-])OC>C1(C)C=CC=CC=1>[CH3:1][C@:2]12[CH2:3][CH2:4][C@H:5]3[C@@H:6]([CH2:12][CH2:13][C:14]4[C@:20]3([CH3:21])[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=4)[C@@H:7]1[CH2:8][CH:9]=[CH:10]2
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Agent: COC(=O)Cl
Agent: COC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: CO
Product: C[C@@]12C=CC[C@H]1[C@@H]1CCC3=CC(=O)CC[C@]3(C)[C@H]1CC2
Yield: 90 %

Procedure:
This synthesis is depicted in FIG. 1. Several methods are known for the conversion of testosterone into Androsta-4,16-dien-3-one (Brooksbank et al, Biochem. J. (1950) AZ:36). Alternatively, thermolysis (460°) of the methyl carbonate of testosterone gives Androsta-4,16-dien-3-one in 90% yield. 17B-MethoxyCarbonyioxy-androst-4-en-3-one (IV) was prepared from testosterone (III. Fluka) with methyl chloroformate/pyridine (a) in 76% yield (after recrystallization from MeOH). M.p. 140-141°, [a]D =+95.4°(c=1.10) IR. (CDCl3):1740s, 1665s, 1450s, 1280s , 1H-NMR. (360 MHz):0.87 (s, 3H); 1.20 (s, 3H); 3.77 (s, 3H); 4.53 (br. t, J 8, 1H); 5.75 (s, 1H). A solution of the methyl carbonate IV in toluene was pyrolyzed (b) as described for I. Recrystallization of the crude product from acetone at RT. gave pure ketone 4 in 90% yield. M.p. 127-129.5°, (a)D +118.90°(C=1.32) ([3]:m.p. 131.5-133.5°(hexane), [a]D16 =+123±3.50°(C=1.03)). IR. (CDCl3):3050w, 1660s, 1615m. 1H-NMR. (360 MHz):0.82 (s, 3H); 1.22 (s, 3H); 5.70 (m, 1H); 5.73 (s, 1H); 5.84 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH2:12])=[C:10]([NH:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH:18](Cl)(Cl)Cl>C(OC(OCC)OCC)C>[Cl:1][C:2]1[C:11]2[N:12]=[CH:18][N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CC(C)CNc1c(N)c(Cl)nc2ccccc12
Reactant: ClC(Cl)Cl
Solvent: CCOC(OCC)OCC
Product: CC(C)Cn1cnc2c(Cl)nc3ccccc3c21
Temperature: 25 °C

Procedure:
A solution of 2-chloro-N4 -(2-methylpropyl)-3,4-quinolinediamine (3 g) in triethylorthoformate (2.8 g) was heated at 80° C. for 15 h. The resulting solution was cooled to ambient temperature and 20 mL of chloroform was added. The solution was washed with water. The product 4-chloro-1-(2-methylpropyl)-1H-imidazo [4,5-c]-quinoline was obtained by concentrating the solution.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])=[CH:10][CH:11]=O.[C:21]([CH:25]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:23][CH3:24])=[O:22]>C(Cl)(Cl)(Cl)Cl.ClCCl>[CH3:24][O:23][C:21](=[O:22])/[CH:25]=[CH:11]/[CH:10]=[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccccc1C(=CC=O)c1ccccc1OC
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)/C=C/C=C(c1ccccc1OC)c1ccccc1OC
Yield: 75.7 %

Procedure:
In the manner described in Example 99, 3,3-bis(2-methoxyphenyl)-2-propenal (7.1 g) was reacted with (carbomethoxymethylene) triphenylphosphorane (9.7 g) in carbon tetrachloride (60 ml) and dichloromethane (20 mL) for 3 days at room temperature and then overnight at reflux. The crude ester isolated in the normal manner was crystallized from 2-propanol-hexane to yield 6.5 g of (E)-5,5-bis(2-methoxyphenyl)-2,4-pentadienoic acid methyl ester, mp 100°-102° C. A portion was recrystallized from the same solvents to furnish the analytical sample, mp 101°-102° C. Anal. Calcd for C20H20O4 : C, 74.06: H, 6.21. Found: C, 73.83; H, 6.23.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH2:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[CH:5]=[N:6][CH:7]=1.Cl[CH2:19][CH2:20][O:21][CH2:22][CH2:23]Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:17]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)([CH3:15])[CH3:16])=[CH:10][CH:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: ClCCOCCCl
Reactant: CC(C)(N)c1ccc(-c2cncc(Br)c2)cc1
Solvent: CN(C)C=O
Product: CC(C)(c1ccc(-c2cncc(Br)c2)cc1)N1CCOCC1

Procedure:
A mixture of 1-[4-(5-bromo-pyridin-3-yl)-phenyl]-1-methyl-ethylamine (Intermediate 229) (1 eq, 1.72 mmol, 500 mg), TEA (3.5 eq, 6.01 mmol, 608 mg), and 2-chloroethyl ether (Sigma-Aldrich, St. Louis, USA) (4 eq, 6.87 mmol, 0.8 ml) in DMF (10 ml) is heated using microwave radiation at 150° C. for 1 h. The mixture is concentrated under reduced pressure, then sat. aqueous NaHCO3 solution is added, followed by extraction with EtOAc. The organic layer is dried with MgSO4, filtered, and the solvents are removed in vacuo. Purification or the crude mixture by column chromatography (hexane/EtOAc) gives the title compound; [M+H]+=361/363.
Reaction SMILES: [C:1]([C:3]1[NH:7][C:6]([CH2:8][CH2:9][CH3:10])=[N:5][C:4]=1[N:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]([O:18][CH3:19])=[O:17])#[N:2].C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:27]2[C:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]3[CH:43]=[CH:42][C:41]([CH2:44]Br)=[CH:40][CH:39]=3)=[N:30][N:29]=[N:28]2)C=CC=CC=1>>[C:1]([C:3]1[N:7]([CH2:44][C:41]2[CH:42]=[CH:43][C:38]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[C:31]3[NH:27][N:28]=[N:29][N:30]=3)=[CH:39][CH:40]=2)[C:6]([CH2:8][CH2:9][CH3:10])=[N:5][C:4]=1[N:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]([O:18][CH3:19])=[O:17])#[N:2]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1nc(-n2cccc2C(=O)OC)c(C#N)[nH]1
Product: CCCc1nc(-n2cccc2C(=O)OC)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Using the procedure from Example 13, methyl 1-(5-cyano-2-propylimidazol-4-yl)-1H-pyrrole-2-carboxylate (Example 34) and N-triphenylmethyl-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole (Example 12) were reacted and deprotected to give the title compound. MS (CI, CH4 +NH3) 507(M+CH3).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[C:9]1([C:15]#[CH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([C:15]#[C:16][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C#Cc1ccccc1
Reactant: Nc1ccc(I)cn1
Product: Nc1ccc(C#Cc2ccccc2)cn1

Procedure:
The title compound, light yellow solid, MS: m/e=195.2 (M+H+), can be prepared in accordance with the general method of example 1 from 2-amino-5-iodopyridine and phenylacetylene.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([Cl:23])=[CH:21][C:20]([Cl:24])=[CH:19][N:18]=4)[CH2:13][CH2:12]3)[NH:7][C:6]=2[CH:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1>>[Cl:23][C:22]1[C:17]([N:14]2[CH2:13][CH2:12][N:11]([C:8]3[NH:9][C:10]4[C:2]([C:35]5[CH:34]=[CH:33][CH:32]=[C:31]([C:30]([F:41])([F:40])[F:29])[CH:36]=5)=[CH:3][C:4]([C:25]([F:27])([F:26])[F:28])=[CH:5][C:6]=4[N:7]=3)[CH2:16][CH2:15]2)=[N:18][CH:19]=[C:20]([Cl:24])[CH:21]=1
Reactant: FC(F)(F)c1cc(Br)c2nc(N3CCN(c4ncc(Cl)cc4Cl)CC3)[nH]c2c1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)cc3nc(N4CCN(c5ncc(Cl)cc5Cl)CC4)[nH]c23)c1

Procedure:
The reaction of 4-bromo-2-[4-(3,5-dichloropyridin-2-yl)piperazin-1-yl]-6-trifluoromethyl-1H-benzoimidazole (99 mg, 0.2 mmol, Example 9) and 3-trifluoromethylphenylboronic acid (48 mg, 0.25 mmol, Aldrich) under the conditions of Example 10 gave the title compound as a light-yellow amorphous solid. MS (ESI, pos. ion) m/z: 560 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:12]=1)=[O:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>C(#N)C>[O:10]=[C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:12]=1)[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCCCn1cc(C(=O)Cc2ccccc2O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCn1cc(C(=O)Cc2ccccc2OCC(=O)OC(C)(C)C)c2ccccc21
Yield: 95.9 %

Procedure:
2-(2-hydroxyphenyl)-1-(1-pentyl-1H-indol-3-yl)ethanone (O-desmethyl JWH-250) 5 (840 mg, 2.61 mmol) was dissolved in acetonitrile (20 ml) followed by the addition of potassium carbonate (1.08 g, 7.83 mmol) and t-butyl bromoacetate (0.76 g, 3.91 mmol). The reaction mixture was heated at reflux overnight. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (Biotage Isolera 4, SNAP-25 g, 0%-10% ethyl acetate in hexane) to give 1.09 g (96%) of t-butyl 2-(2-(2-oxo-2-(1-pentyl-1H-indol-3-yl)ethyl)phenoxy)acetate (O-desmethyl JWH-250 t-Butyl 2-CME) 6.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]([C:16]#[N:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[CH2:8]Br.[C:18]([O-:21])(=[O:20])[CH3:19].[K+]>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]([C:16]#[N:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][O:21][C:18](=[O:20])[CH3:19]
Reactant: CC(=O)[O-]
Reactant: N#Cc1ccccc1-c1ccc(CBr)c(Br)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCc1ccc(-c2ccccc2C#N)cc1Br
Temperature: 50 °C
Yield: 64.1 %

Procedure:
To a solution of 662 mg (1.89 mmol) of 3'-bromo-4'-bromomethyl-1,1'-biphenyl-2-nitrile (Step D) in 10 mL of dry dimethyl formamide was added 925 mg (9.43 mmol) of potassium acetate. The reaction mixture was heated at 50° C. for 2 hours then diluted with 100 mL of water. The mixture was extracted with ethyl acetate (3×100 mL). The organic extracts were combined, washed with water (100 mL), saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL). The solution was dried over magnesium sulfate, filtered and the solvent removed under vacuum to give an oil which was purified by flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (75:25), to afford 400 mg (64%) of the product as a white solid. 1H NMR (200 MHz, CDCl3): δ 2.14 (s, 3H), 5.22 (s, 2H), 7.4-7.8 (m, 7H). EI-MS: calculated for C16H12BrNO2 329; found 329, 331 (M+, 7%); 270, 272 (M-Br, 100%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:11]=3)([CH3:4])([CH3:3])[CH3:2].CCCCCC.C([Li])CCC.[C:33]([C:37]1[CH:38]=[CH:39][C:40](=[C:42]([CH3:44])[CH3:43])[CH:41]=1)([CH3:36])([CH3:35])[CH3:34]>CCOCC.O>[C:33]([C:37]1[CH:38]=[CH:39][CH:40]([C:42]([C:11]2[C:10]3[CH2:9][C:8]4[C:16](=[CH:17][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=4)[C:15]=3[CH:14]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=2)([CH3:44])[CH3:43])[CH:41]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)=C1C=CC(C(C)(C)C)=C1
Reactant: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)ccc1C2
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(C)C1=CC(C(C)(C)c2cc(C(C)(C)C)cc3c2Cc2ccc(C(C)(C)C)cc2-3)C=C1
Temperature: 25 °C
Yield: 43.1 %

Procedure:
To a solution of 1.98 g (7.1 mmol) of 3,6-di-tert-butylfluorene in 40 ml of ether, 4.6 ml (7.5 mmol) of a hexane solution of n-butyllithium was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for one night. To the resulting red solution, a solution of 1.56 g (9.6 mmol) of 3-tert-butyl-6,6-dimethylfulvene in 20 ml of ether was further dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for one night. Then, 60 ml of water was added. The separated organic phase was dried over magnesium sulfate and then filtered. From the filtrate, the solvent was removed under reduced pressure to obtain a solid. The solid was purified by column chromatography (silica gel, developing solvent: hexane) to obtain 1.35 g of a light yellow solid (yield: 43%). The analyzed values are given below.