Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:24][C:25]1[CH:30]=[C:29]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH:28]=[CH:27][C:26]=1[NH:39][CH2:40][C:41]1[CH:50]=[CH:49][C:44]([C:45]([O:47][CH3:48])=[O:46])=[C:43]([O:51][CH3:52])[CH:42]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C=O)C>[Si:32]([O:31][C:29]1[CH:28]=[CH:27][C:26]([NH:39][CH2:40][C:41]2[CH:50]=[CH:49][C:44]([C:45]([O:47][CH3:48])=[O:46])=[C:43]([O:51][CH3:52])[CH:42]=2)=[C:25]([NH:24][C:13](=[O:15])[C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:17][CH:16]=2)[CH:30]=1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: COC(=O)c1ccc(CNc2ccc(O[Si](C)(C)C(C)(C)C)cc2N)cc1OC
Reactant: O=C(O)c1ccc(OCCN2CCCC2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(CNc2ccc(O[Si](C)(C)C(C)(C)C)cc2NC(=O)c2ccc(OCCN3CCCC3)cc2)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
To 4-[2-(1-pyrrolidinyl)ethoxy]benzoic acid (350 mg, 1.29 mmol) in CH2Cl2 (2 ml) was added oxalyl chloride (327 mg, 2.58 mmol) and a catalytic amount of DMF. The mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. The acid chloride was dried, under vacuum, overnight. To the aniline (Example 1, Part D; 0.49 g, 1.17 mmol), in pyridine (0.158 g, 2.34 mmol) and CH2Cl2 (3 mL) at 0° C. and under N2, was added the previously formed acid chloride (see Example 5, Part D) in 4 mL CH2Cl2 dropwise. Upon completion of addition, the mixture was stirred for 15 minutes at room temperature and then the reaction quenched by the addition saturated NaHCO3. Product was extracted with EtOAc, the organics washed with H2O, and concentrated under reduced pressure; yielding 583 mg of desired product after flash chromatography (SiO2, 10% MeOH in CHCl3).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](Cl)=[O:15]>C(Cl)Cl.O>[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:15]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccccc1)c1cccc(Cl)c1
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a solution of aniline (178 mg, 1.9 mmol) in 20 mL CH2Cl2 at room temperature was added NaOH (76.2 mg, 2.9 mmol) in 6 mL water. This mixture was stirred vigorously for 5 minutes after which 3-chlorobenzoyl chloride (500 mg, 2.9 mmol) was added drop-wise while stirring over a period of 30 minutes. This reaction mixture was stirred for an additional 2 hours followed by an acid work-up and extraction with CH2Cl2 (3×20 mL). The organic layers were combined, dried over anhydrous MgSO4. The product was purified via column chromatography on silica gel and eluted with a CHCl3/MeOH/Et3N (9.8:0.1:0.1) to give white crystals in 81% yield.
Reaction SMILES: [K].[CH3:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)=[O:4].Br[CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15].C(Cl)Cl>CN(C)C=O.O>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])=[CH:7][CH:6]=1)(=[O:4])[CH3:2]
Reactant: COC(=O)C(C)Br
Reactant: CC(=O)c1ccc(O)cc1
Agent: [K]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(C)Oc1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.5 %

Procedure:
To a solution of the potassium salt of 4-hydroxyacetophenone (8.8 g, 0.05 mol) in dimethylformamide (25 mL) is added methyl 2-bromopropanoate (10.2 g, 0.06 mol) over 30 minutes and stirred at 80°-90° C. for 4 hours under nitrogen. The reaction is cooled to room temperature and methylene chloride (75 mL) and water (75 mL) are added. The organic phase is separated, washed with water (100 mL), dried and concentrated to give methyl 2-(4-acetylphenoxy)propanoate (8.5 g) (yield 76%). Methyl 2-(4-acetylphenoxy)propanoate (7.0 g, 31.5 mmol) is combined with 2N NaOH (20 mL) and refluxed overnight. Water (30 mL) is added to the reaction which is then washed with methylene chloride (50 mL). It is then acidified to pH=1 with concentrated hydrochloric acid and extracted with ethyl acetate (3×100 mL). The organic phase is dried and concentrated to provide 2-(4-acetylphenoxy)propanoic acid (5.0 g) (yield 92%): m.p. 104.3° C., IR (KBr) 3000 (br, vs), 2940 (br,s), 1754 (vs), 1650 (vs); 1H NMR (CDCl3) delta 1.69 (d, J=6.8 Hz, 3H), 2.55 (s, 3H), 4.8 (q, J=6.8 Hz, 1H), 6.92 and 7.93 (dd, J=9.0 Hz, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14]2[N:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16]([C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([OH:27])=O)[CH:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[NH2:53][CH2:54][CH2:55][N:56]1[CH2:60][CH2:59][CH2:58][CH2:57]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14]2[N:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16]([C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([NH:53][CH2:54][CH2:55][N:56]3[CH2:60][CH2:59][CH2:58][CH2:57]3)=[O:27])[CH:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1nc(NCCc2ccc(OC)c(OC)c2)cc(-c2cccc(C(=O)O)c2)n1
Reactant: NCCN1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1nc(NCCc2ccc(OC)c(OC)c2)cc(-c2cccc(C(=O)NCCN3CCCC3)c2)n1
Yield: 23.7 %

Procedure:
A solution of 3-{6-[2-(3,4-dimethoxy-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-benzoic acid [0.15 mmol, Example 35(k)], hydroxybenzotriazole (41 mg, 0.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (58 mg, 0.3 mmol), N-(2-aminoethyl)pyrrolidine (38 μL, 0.3 mmol) and N,N-diisopropylethylamine (105 μL, 0.6 mmol) in DCM (3 mL) is stirred at ambient temperature under a nitrogen atmosphere for 18 hours. The reaction is poured into water (20 mL) and extracted twice with EtOAc (25 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated by rotary evaporator. The resulting solid is subjected to flash column chromatography on silica gel eluting with 10 to 60% EtOAc in heptane gradient to afford 3-{6-[2-(3,4-dimethoxy-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide [18 mg, 24%, Example 25(b)]. LCMS: RT=2.1 minutes, MS: 506 (M+H). IC50=30 nM
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([N:19]1[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1.Cl.C(OCC)(=O)C>[C:11]([N:19]1[CH2:24][CH2:23][C:22]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]1)(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)C1CCN(C(=O)c2ccccc2)CC1
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2ccccc2)CCN(C(=O)c2ccccc2)CC1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
A stirred solution of 176 mL of commercial 1M lithium bistrimethylsilylamide in tetrahydrofuran was diluted with 100 mL of tetrahydrofuran and cooled to -78° C. under inert atmosphere. A solution of 44 g of ethyl 1-benzoyl-4-piperidinecarboxylate in 200 mL of tetrahydrofuran was added dropwise keeping the temperature below -60° C., followed by 21 mL of benzyl bromide. The resulting mixture was allowed to warm and stir overnight, diluted with 200 mL of 1N hydrochloric acid, 200 mL of ethyl acetate and separated. The organic layer was washed with 200 mL of 1N hydrochloric acid, dried over MgSO4, and concentrated. The residue was dissolved in 300 mL of toluene, filtered and concentrated under reduced pressure. Drying under reduced pressure gave 56.3 g of ethyl 1-benzoyl-4-(phenylmethyl)-4-piperidinecarboxylate as a viscous oil homogeneous by thin layer chromatography, eluting with 1:1 ethyl acetate: hexane, 1H NMR (300 MHz, CDCl3) 1.20 (t, 3H), 1.40 (m, 1H), 1.60 (m, 1H), 2.07 (m, 1H), 2.22 (m, 1H), 2.85 (d, 2H), 3.08 (m, 1H), 3.65 (m, 1H), 4.12 (q, 2H), 4.65 (m, 1H), 7.04 (m, 2H), 7.24 (m, 3H), 7.38 (m, 5H).
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1>Br.CC(O)=O>[F:17][C:15]([F:16])([F:18])[C:14]1[C:9]([C:6]2[CH:5]=[CH:4][C:3](=[O:2])[NH:8][CH:7]=2)=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: COc1ccc(-c2ncccc2C(F)(F)F)cn1
Agent: Br
Solvent: CC(=O)O
Product: O=c1ccc(-c2ncccc2C(F)(F)F)c[nH]1
Reaction time: 1 h
Yield: 93.7 %

Procedure:
Heat 6′-Methoxy-3-trifluoromethyl-[2,3′]bipyridinyl (41 g, 0.16 mol) in 30% HBr/AcOH (100 mL) to reflux for 1 hour. Cool the mixture, filter and wash the precipitate with ether (100 mL). Transfer the precipitate into 10M sodium hydroxide (500 mL) and stir for 1 hour. Treat the solution with hydrochloric acid until the solution is pH 7. Collect the white solid by filtration and air dry to give the title compound (36 g, 93%) as a white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]([CH3:16])=[CH2:15])[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].[ClH:17].O>C(Cl)(Cl)(Cl)Cl.[Cl-].C([N+](CCCCCCCC)(CCCCCCCC)C)CCCCCCC>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]([Cl:17])([CH3:16])[CH3:15])[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: C=C(C)COc1cc(OCC#CC)ncn1
Reactant: Cl
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC#CCOc1cc(OCC(C)(C)Cl)ncn1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
In 1.2 ml of carbon tetrachloride were dissolved 0.15 g of 4-(2-butynyloxy)-6-(2-methylallyloxy)pyrimidine and 0.01 g of trioctylmethylammonium chloride, to which 1 ml of concentrated hydrochloric acid was added dropwise at 0° C., followed by stirring at 0° C. for 30 minutes and at room temperature for 50 minutes. The reaction mixture was then poured into water, which was extracted three times with t-butyl methyl ether. The combined organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution, a saturated aqueous sodium chloride solution, dried over anhydrous magnesium, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.08 g of 4-(2-butynyloxy)-6-(2-chloro-2-methylpropyloxy)pyrimidine (the present compound (20)).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[CH3:13][C:14]1[CH:19]=[C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:17]=[CH:16][C:15]=1[NH2:26].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([NH:26][C:15]1[CH:16]=[CH:17][C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:19][C:14]=1[CH3:13])=[O:7]
Reactant: Cc1cc(N2CCOCC2)ccc1N
Reactant: COc1ccc(C(=O)O)cc1Br
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2C)cc1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3-bromo-4-methoxy-benzoic acid (247 mg), 2-methyl-4-morpholin-4-yl-phenylamine (205 mg), EDAC (410 mg), HOBT (289 mg) and N-methylmorpholine (353 μl) in DMF (5 ml) was stirred at room temperature for 18 h. The mixture was then diluted with water (30 ml) and the resulting solid collected by filtration and dried (464 mg)
Reaction SMILES: [I:1]Cl.[Cl:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1[Cl:11])[NH2:7]>C(O)(=O)C>[Cl:11][C:10]1[C:4]([Cl:3])=[CH:5][C:6]([NH2:7])=[C:8]([I:1])[CH:9]=1
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: ClI
Solvent: CC(=O)O
Product: Nc1cc(Cl)c(Cl)cc1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
Iodine monochloride (1.39 mL; 27.77 mmol) was added to a solution of 3,4-dichloroaniline (4.50 g; 27.77 mmol) in acetic acid (15 mL) and the resulting mixture was stirred for 30 minutes at room temperature. The solution was concentrated to dryness, neutralized with sodium bicarbonate and extracted with dichloromethane. The combined organic layers were washed with a saturated solution of sodium thiosulfate, dried and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in heptane) to afford 3.46 g (43%) of the title compound as a brown solid.
Reaction SMILES: [NH2:1][CH:2]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH2:3][CH2:4][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1.C(N(CC)CC)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1.O>C(Cl)Cl>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([NH:1][CH:2]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:3][CH2:4][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=2)(=[O:40])=[O:39])=[CH:34][CH:33]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)COc1ccc(CCC(N)c2cccnc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1ccc(CCC(NS(=O)(=O)c2ccc(Cl)cc2)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 28.3 %

Procedure:
Ethyl 4-[3-amino-3-(3-pyridyl)propyl]phenoxyacetate (50 mg) and 30 mg of triethylamine were dissolved in 10 ml of methylene chloride, followed by addition of 50 mg of p-chlorobenzene sulfonylchloride, and stirred at room temperature for 2.5 hours. To the reaction mixture was added water, and the organic phase was then separated which was extracted with methanol-methylene chloride (5:95 v/v) from the aqueous phase. The organic phases were combined and washed in saturated aqueous sodium chloride followed by drying over magnesium sulfate and distillation of the solvent. The obtained residue was subjected to chromatography on a silica gel column, and from a fraction eluted with methanol-methylene chloride (5:95 v/v) was obtained 22 mg of ethyl 4-[3-(4-chlorobenzenesulfonamido)-3-(3-pyridyl)propyl]phenoxyacetate. The spectrometric data supports the structure of [38] as follows.
Reaction SMILES: CN(C)C=O.[O:6]1[CH2:10][CH2:9][O:8][CH:7]1[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][OH:18])=[N:15][CH:16]=1.[H-].[Na+].F[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>O>[O:6]1[CH2:10][CH2:9][O:8][CH:7]1[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][O:18][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[N:15][CH:16]=1
Reactant: OCc1ccc(C2OCCO2)cn1
Reactant: Fc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(OCc2ccc(C3OCCO3)cn2)nc1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 77.3 %

Procedure:
To an N,N-dimethylformamide (40 mL) solution of (5-[1,3]dioxolan-2-yl-pyridin-2-yl)-methanol (1.37 g, 7.56 mmol) described in Manufacturing Example 154-1-4 was added sodium hydride (333 mg, 8.32 mmol, 60% in oil), which was sbrred for 5 minutes at 0° C. Next, 2-fluoropyridine (716 μL, 8.32 mmol) was added to the reaction mixture, which was stirred for 45 minutes at 50° C. Water was added to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1 to 1:1) to obtain the title compound (1.51 g, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([NH2:11])=[CH:8][C:9]=1[Cl:10])[CH:5]=O.C[C:13](C)([C:17]([O-:19])=[O:18])[C:14]([O-:16])=O.[CH2:21](OCC)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:7](=[CH:8][C:9]=1[Cl:10])[N:11]=[C:14]([OH:16])[C:13]([C:17]([O:19][CH3:21])=[O:18])=[CH:5]2
Reactant: CCOCC
Reactant: Nc1cc(Cl)c(Cl)cc1C=O
Reactant: CC(C)(C(=O)[O-])C(=O)[O-]
Product: COC(=O)c1cc2cc(Cl)c(Cl)cc2nc1O

Procedure:
3,4-Dichloro-6-aminobenzaldehyde (2.85 g, 15 mmol) was stirred with dimethylmalonate (10 ml) at 140° C. for 20 h. The mixture was diluted with ethyl ether (100 ml). The precipitate was collected, washed twice with ethyl ether and dried in vacuo to give 2.86 g of methyl 6,7-dichloro-2-hydroxyquinoline-3-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[CH2:9](Br)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[OH-].[Na+]>O>[CH2:9]([S:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCBr
Reactant: Sc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCSc1ccc(Br)cc1
Yield: 85 %

Procedure:
4-Bromothiophenol (15 g, 0.0794 m) was stirred and heated at 80° C. for 18 hours with n-heptylbromide (14.9 g, 0.0833 m) sodium hydroxide (3.3 g, 0.0833 m) and water (15 mls). The mixture was then added to water (50 mls) and extracted with petroleum spirit 400°-60° (3×50 mls). The combined organic phase was dried over magnesium sulphate and evaporated to yield 4-n-heptylthiobromobonzene (19.5 g, 89% GLC, 85% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([O:31][CH2:32][CH2:33]O)=[CH:23][CH:22]=1>CN(C)C=O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:33][CH2:32][O:31][C:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:21]=[CH:22][CH:23]=2)=[CH:7][CH:6]=1
Reactant: OCCOc1ccnc2ccccc12
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccnc3ccccc23)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 56.9 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (1.267 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.305 g), stirred for 15 minutes and treated with the mesylate prepared from 1.135 g of 2-(4-quinolyloxy)ethanol. The mixture was heated under argon at 60° C. for 3 hours. The cooled mixture was treated with glacial acetic acid (2 drops) and the volatiles were removed under vacuum. The residue was mixed with dichloromethane and dilute cold sodium bicarbonate solution. The dichloromethane extracts were washed with water, dried (Na2SO4), filtered, and evaporated to give crude product. The material was purified by HPLC (ethyl acetate-methanol; 20: 1) and crystallized from dichloromethane-hexane to provide 1.2 g of alpha-oxo-4-[[2-(4-quinolyloxy)ethyl]oxy]benzeneacetic acid methyl ester as a colorless solid, mp 135°-136° C.
Reaction SMILES: Br[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[C:10]1([N:16]2[C:24](=[O:25])[C:23]3[C@@H:22]4[C:26]([CH3:28])([CH3:27])[C@@:19]([CH3:29])([CH2:20][CH2:21]4)[C:18]=3[NH:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CC(C)=O.CO>[CH2:2]([N:17]1[C:18]2[C@@:19]3([CH3:29])[C:26]([CH3:28])([CH3:27])[C@H:22]([CH2:21][CH2:20]3)[C:23]=2[C:24](=[O:25])[N:16]1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH3:3]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3)c(=O)c12
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)=O
Product: CCn1c2c(c(=O)n1-c1ccccc1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 25 °C
Yield: 8.7 %

Procedure:
A mixture of bromoethane (1.05 mL, 14.1 mmol), potassium carbonate (3.58 g, 25.9 mmol), and (4S,7R)-2-phenyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 6; 1.74 g, 6.5 mmol) in acetone (20 mL) and methanol (3 mL) was stirred at room temperature over the weekend then the solvent was evaporated and the residue was partitioned between water and dichloromethane. The organic layer was evaporated, and the residue was chromatographed (0-50% ethyl acetate/hexanes) and recrystallized from ethyl acetate to give (4S,7R)-1-ethyl-7,8,8-trimethyl-2-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (168 mg, 9%) as a white solid. APCI-MS (M+H) 297.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:24])[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH2:15][O:16][CH2:17][CH2:18][N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH3:14])=[CH:4][CH:3]=1.[C:25]([O-:28])([O-])=[O:26].[K+].[K+].BrCC[CH:34]=[C:35]1[C:41]2C=CC=NC=2COC2C=CC(C(O)(C)C)=C[C:36]1=2>C(#N)C.O>[C:35]([O:28][C:25]([N:11]1[CH2:12][CH2:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)([OH:24])[C:9]([CH2:15][O:16][CH2:17][CH2:18][N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])([CH3:14])[CH2:10]1)=[O:26])([CH3:41])([CH3:36])[CH3:34]
Reactant: CCN(CC)CCOCC1(C)CNCCC1(O)c1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCN(CC)CCOCC1(C)CN(C(=O)OC(C)(C)C)CCC1(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-(4-chloro-phenyl)-3-(2-diethylamino-ethoxymethyl)-3-methyl-piperidin-4-ol in acetonitrile/water (8:2) (3.2 mL) was added K2CO3 and 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1 aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol. The solution was allowed to stir at room temperature for 48 h. The reaction was concentrated down and partitioned between EtOAc/H2O, extracted with EtOAc (3×). The organics were collected, dried over MgSO4, filtered and evaporated in vacuo, then purified by Biotage flash chromatography (5% methanol/95% methylene chloride to 10% methanol/90% methylene chloride to 15% methanol/85% methylene chloride) to yield the title compound. 1H-NMR (CDCl3): 0.50 (s, 3H), 0.97 (t, 6H), 1.52 (s, 6H), 2.40–2.66 (m, 12H), 3.16–3.30 (m, 6H), 5.32 (bs, 2H), 6.06 (t, 1H), 6.80 (t, 1H), 7.20 (dd, if H), 7.29 (dd, 1H), 7.29–7.31 (m, 6H), 7.58 (d, 2H), 8.51 (d, 1H). δ ESI-MS m/z: 648 (M+1), retention time 1.19.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].C(=O)(O)[O-].[Na+].[Br:19][CH2:20][C:21](Br)=[O:22]>C(Cl)(Cl)Cl>[Br:19][CH2:20][C:21]([NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:10])([F:11])[F:12])[CH:5]=[CH:4][C:3]=1[OH:13])=[O:22]
Reactant: Nc1cc(OC(F)(F)F)ccc1O
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C(CBr)Nc1cc(OC(F)(F)F)ccc1O
Temperature: 0 °C
Yield: 87.1 %

Procedure:
2-amino-4-[(trifluoromethyl)oxy]phenol (3.0 g, 15.5 mmol) was dissolved in 100 mL of chloroform. 54 mL of saturated sodium bicarbonate solution was added and the new bi-phase mixture was stirred vigorously and cooled to 0° C. using an ice bath. Bromoacetylbromide (2.1 mL, 23.3 mmol) was added drop-wise. Fifteen minutes later the solution was removed from the ice bath and maintained at room temperature for 2 hours before it was determined to be complete by LCMS (two Aquasil C18, 20×1 mm columns were run in sequence, 4 minutes at 0.1 mL/min, 1-99% CH3CN/H2O with 0.018% trifluoroacetic acid, ES) Rt=1.77 min and m/e 314 [M+1]+. The organic layer was separated and the aqueous phase was extracted with 100 mL of chloroform. The combined organic phases were dried over Na2SO4, filtered and concentrated to give 2-bromo-N-{2-hydroxy-5-[(trifluoromethyl)oxy]phenyl}acetamide (4.23 g, 13.5 mmol, 87%) as a brown amorphous solid. MS (ES) m/e 314 [M+H]+.