Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC1C=CC(C(C2C=C(OC)C=CC=2C2C=CC3C(=CC=C(OC)C=3)C=2)=O)=CC=1.Cl.ClCCN1CCCCCC1.[N:41]1([CH2:48][CH2:49][O:50][C:51]2[CH:56]=[CH:55][C:54]([C:57]([C:59]3[CH:64]=[C:63]([O:65][CH3:66])[CH:62]=[CH:61][C:60]=3[C:67]3[CH:76]=[CH:75][C:74]4[C:69](=[CH:70][CH:71]=[C:72]([O:77][CH3:78])[CH:73]=4)[CH:68]=3)=O)=[CH:53][CH:52]=2)[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>>[CH3:66][O:65][C:63]1[CH:62]=[CH:61][C:60]([C:67]2[CH:76]=[CH:75][C:74]3[C:69](=[CH:70][CH:71]=[C:72]([O:77][CH3:78])[CH:73]=3)[CH:68]=2)=[C:59]([CH:64]=1)[CH2:57][C:54]1[CH:55]=[CH:56][C:51]([O:50][CH2:49][CH2:48][N:41]2[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]2)=[CH:52][CH:53]=1
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2)c(C(=O)c2ccc(OCCN3CCCCCC3)cc2)c1
Agent: COc1ccc(-c2ccc3cc(OC)ccc3c2)c(C(=O)c2ccc(O)cc2)c1
Agent: Cl
Agent: ClCCN1CCCCCC1
Product: COc1ccc(-c2ccc3cc(OC)ccc3c2)c(Cc2ccc(OCCN3CCCCCC3)cc2)c1
Yield: 72 %

Procedure:
Synthesized from (4-hydroxyphenyl)[5-methoxy-2-(6-methoxynaphthalen-2-yl)phenyl]methanone and 1-(2-chloroethyl)azepane hydrochloride according to an analogous synthetic method to Preparation Example 40, [4-(2-azepan-1-ylethoxy)phenyl][5-methoxy-2-(6-methoxynaphthalen-2-yl)phenyl]methanone (1.0 g) was used according to an analogous synthetic method to Example 337 described below to provide 1-{2-{4-[5-methoxy-2-(6-methoxynaphthalen-2-yl)benzyl]phenoxy}ethyl}azepane (700 mg). This compound (421 mg) was used according to an analogous synthetic method to Example 111 described below to provide the title compound (105 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[N+:10]([O-])=O.O.O.[Sn](Cl)Cl>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[NH2:10]
Reactant: COc1cc(C)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: COc1cc(C)ccc1N

Procedure:
To a solution of 2-methoxy-4-methyl-1-nitrobenzene (5 g; 29.9 mmol) in methanol (200 mL) was added Tin(II) chloride dihydrate (33.7 g; 150 mmol) and the mixture was heated to reflux for 3 h. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate. A saturated solution of sodium hydrogen carbonate was added until pH 8. A suspension formed and the mixture was filtered on a plug of celite. The organic phase was separated, washed with a saturated solution of sodium hydrogen carbonate solution and dried over magnesium sulphate. The solvent was removed under reduced pressure and the residue was used as such in the next reaction.
Reaction SMILES: [F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@@H:14]([CH3:26])[C@:15]3([OH:25])C(=O)CO)[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:28])[CH:4]=[CH:5][C:6](=[O:27])[CH:7]=1.[O-][Bi](=O)=O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@@H:14]([CH3:26])[C:15]3=[O:25])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:28])[CH:4]=[CH:5][C:6](=[O:27])[CH:7]=1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO
Agent: O=[Bi](=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)C1=O
Yield: 81.6 %

Procedure:
A solution of 33 g (84.09 mmole) of 9-fluoro-16α-methyl-11β,17,21-trihydroxypregna-1,4-diene-3,20-dione in 50% acetic acid (3 liters) was stirred with 320 g of sodium bismuthate at room temperature for 20 hours. The resulting brown suspension was filtered through a bed of deactivated silica powder and washed with 300 ml of 50% acetic acid. The filtrate was concentrated in vacuo to 500 ml, diluted with 250 ml of 20% hydrochloric acid and extracted with chloroform. The chloroform solution was washed with 20% hydrochloric acid and water, dried over anhydrous Na2SO4 and evaporated in vacuo to give a solid. This was dissolved in chloroform and chromatographed on a 250 g-silica gel column, eluting successively with chloroform and 1:4 ethyl acetate-chloroform to give 22.8 g (81.6%) of tlc-homogeneous title compound, melting point 240°-242° with consistent spectral data.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[C:19]([CH3:27])[CH:18]=3)[N:8]=2)[CH:6]=1.[C:28]([NH:32][S:33]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)(=[O:35])=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([NH:32][S:33]([C:36]1[CH:41]=[CH:40][C:39]([C:2]2[N:3]=[CH:4][N:5]([C:7]3[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:26])[F:24])=[C:19]([CH3:27])[CH:18]=4)[N:8]=3)[CH:6]=2)=[CH:38][CH:37]=1)(=[O:35])=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(-c4ccc(S(=O)(=O)NC(C)(C)C)cc4)c3)n2)ccc1C(F)(F)F

Procedure:
N-tert-Butyl-4-{1-[6-(3-methyl-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide was prepared from 2-(4-iodo-imidazol-1-yl)-6-(3-methyl-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidine (example E.73) (0.50 g, 1.0 mmol) and commercially available 4-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.057 g), which was subsequently deprotected.
Reaction SMILES: C([O:5][C:6](=[O:22])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][C:10]=1Br)(C)(C)C.[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])[CH:26]=1)#[CH:24]>>[CH2:34]([S:31]([C:27]1[CH:26]=[C:25]([C:23]#[C:24][C:10]2[CH:11]=[C:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]([OH:5])=[O:22])[CH:30]=[CH:29][CH:28]=1)(=[O:33])=[O:32])[CH2:35][CH3:36]
Reactant: C#Cc1cccc(S(=O)(=O)CCC)c1
Reactant: CC(C)(C)OC(=O)COc1ccc(-c2ccccc2)cc1Br
Product: CCCS(=O)(=O)c1cccc(C#Cc2cc(-c3ccccc3)ccc2OCC(=O)O)c1

Procedure:
Following the general method as outlined in Example 37, starting from tert-butyl[(3-bromobiphenyl-4-yl)oxy]acetate (Intermediate 188) and 1-ethynyl-3-(propane-1-sulfonyl)-benzene (Intermediate 42), the title compound was obtained as a beige solid after purification by preparative HPLC.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:30]>ClCCl>[Br:30][CH2:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cccc(CO)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cccc(CBr)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
To an ice cooled a solution of (6-methylpyridin-2-yl)methanol (400 mg, 3.25 mmol) in dichloromethane (16 mL) under an atmosphere of dry nitrogen was added triphenylphosphine (1278 mg, 4.87 mmol) and carbon tetrabromide (1616 mg, 4.87 mmol). The mixture was stirred for 1 hour. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica, eluting with 2-4% methanol in dichloromethane to give 2-(bromomethyl)-6-methylpyridine as an oil (402 mg).
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH2:21].[I:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>ClCCl>[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH:21][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=1[I:22]
Reactant: O=C(Cl)c1ccccc1I
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.3 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide was prepared according to method C with triethylamine (1.19 mL; 8.48 mmol), 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.800 g; 3.90 mmol) and 2-iodobenzoyl chloride (0.968 g; 3.56 mmol) in dichloromethane (75 mL). The mixture was stirred for 20 minutes at room temperature and was evaporated to dryness. The crude material was purified by flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) to furnish 1.32 g (92%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide as a white solid.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH:17]([CH:22](O)[CH3:23])[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].CS(Cl)(=O)=O>C(Cl)Cl>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18](=[O:21])[C:17](=[CH:22][CH3:23])[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC=C1CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
0.77 g (7.6 mmol) of triethylamine were added to a 20 ml methylene chloride solution of 1.86 g (7.6 mmol) of the 1-(t-butoxycarbonyl)-3-(1-hydroxyethyl)-4-piperidone obtained above. Under ice cooling, 0.88 g (7.6 mmol) of methanesulfonyl chloride were added and the resulting mxiture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue. The solid thus precipitated was filled out, followed by concentration under reduced pressure again. The concentrate was then dissolved in 20 ml of chloroform, followed by the addition of 1.16 g (7.6 mmol) of 1,8-diazabicyclo[5.4.0]under-7-ene (DBU) at room temperature. The mixture was stirred for 2 hours at the same temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column (eluting solvent: toluene/ethyl acetate=19/1), whereby 1.32 g (yield: 77.2%) of the title compound were obtained as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CO.CN(C)C=O>[O:21]=[C:20]1[C:4]2[C:5]3[C:6](=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]=3[CH:10]=[C:2]([NH:1][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=3[C:23]([F:22])([F:33])[F:34])[CH:3]=2)[CH:17]=[N:18][NH:19]1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: O=C(O)c1ccccc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O)c1ccccc1C(F)(F)F
Yield: 46.5 %

Procedure:
Preparation of example 42 from the title compound of Example 7 (0.1 g, 0.36 mmol), 2-Trifluoromethyl-benzoic acid (0.103 g, 0.54 mmol), triethylamine (0.2 mL, 1.45 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.207 g, 0.54 mmol) and N,N-dimethylformamide (0.1 M, 3.6 mL) was carried out analogously to Example 11. Silica gel chromatography (95:5 CH2Cl2/methanol) afforded the title compound (0.075 g) as a yellow powder in 46% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>CN(C=O)C.C(OCC)(=O)C>[CH3:21][N:22]([CH3:24])[CH:23]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=1)=[O:10]
Reactant: COC(OC)N(C)C
Reactant: CSc1ccc(C(=O)Cc2ccc(F)cc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1ccc(C(=O)C(=CN(C)C)c2ccc(F)cc2)cc1

Procedure:
2-(4-Fluorophenyl)-1-[4-(methylthio)phenyl]ethanone from Example 1, Step 1 (17.2 g, 66 mmol) was stirred with 15 mL dimethylformamide dimethylacetal in 80 mL dry DMF at 120° C. for 24 hours under nitrogen. The reaction mixture was cooled, diluted with two volumes of ethyl acetate, and the solution washed successively with water and brine and dried over Na2SO4. The solvent was removed under high vacuum and the resulting brown oil (23.9 g) was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C:11](=[O:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[H-].C([Al+]CC(C)C)C(C)C>C1COCC1.C1(C)C=CC=CC=1>[CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16]4[C:17](=[CH:18][O:19][C:20]=4[C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[O:3]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CCC(=O)[C@@]2(C)C[C@H]1OC(C)=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of wortmannin (100 mg) stirring in THF at -78° C. was added diisobutylaluminum hydride (0.4 mL of a 1.0M solution in toluene, 0.4 mmol). After 0.5 hour, the reaction was quenched with saturated aqueous NaHCO3. The mixture was then warmed to room temperature and extracted with CH2Cl2. The combined organic extracts were washed with brine and dried (MgSO4). The crude material was purified by radial chromatography (SiO2, 4 mm, 9:1 EtOAc/Hexanes) to give a 70% yield of 17β-hydroxywortmannin as an off-white powder.
Reaction SMILES: O[CH:2]([C:4]1[C:5]([CH3:31])=[CH:6][C:7]([O:29][CH3:30])=[C:8]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[CH:20]=3)[CH2:15][CH2:14]2)=[O:12])[CH:9]=1)[CH3:3].C1C=CC(N=NC2C=CC(N)=NC=2N)=CC=1.Cl.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[CH3:30][O:29][C:7]1[CH:6]=[C:5]([CH3:31])[C:4]([CH:2]=[CH2:3])=[CH:9][C:8]=1[NH:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:20]=[C:21]([O:27][CH3:28])[CH:22]=[C:23]([O:25][CH3:26])[CH:24]=2)[CH2:15][CH2:14]1)=[O:12]
Reactant: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc(C(C)O)c(C)cc3OC)CC2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: Nc1ccc(N=Nc2ccccc2)c(N)n1
Solvent: ClC(Cl)Cl
Product: C=Cc1cc(NC(=O)N2CCN(c3cc(OC)cc(OC)c3)CC2)c(OC)cc1C
Yield: 84 %

Procedure:
1-{[5-(1-Hydroxyethyl)-2-methoxy-4-methylphenyl]aminocarbonyl}-4-(3,5-dimethoxyphenyl)piperazine(0.2 g, 0.47 mmol) was dissolved in chloroform(15 ml), pyridium p-toluenesulfonate(0.12 g, 0.47 mmol) was added thereto, and the resulting mixture was refluxed for 16 hours, and concentrated under the reduced pressure to remove chloroform and purified by column chromatography(ethylacetate:hexane=1:2) to obtain the titled compound.
Reaction SMILES: Cl.[N:2]1([CH:8]2[CH2:20][CH2:19][C:18]3[C:10](=[CH:11][C:12]4[C:13]([CH:17]=3)=[N:14][O:15][N:16]=4)[CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:22][CH2:23][C:24]1[CH:33]=[CH:32][C:27]2[C:28](=[O:31])[O:29][CH2:30][C:26]=2[CH:25]=1.C(N(CC)CC)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[N:14]1[O:15][N:16]=[C:12]2[CH:11]=[C:10]3[C:18]([CH2:19][CH2:20][CH:8]([N:2]4[CH2:3][CH2:4][N:5]([CH2:22][CH2:23][C:24]5[CH:33]=[CH:32][C:27]6[C:28](=[O:31])[O:29][CH2:30][C:26]=6[CH:25]=5)[CH2:6][CH2:7]4)[CH2:9]3)=[CH:17][C:13]=12
Reactant: O=C1OCc2cc(CCBr)ccc21
Reactant: c1c2c(cc3nonc13)CC(N1CCNCC1)CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1OCc2cc(CCN3CCN(C4CCc5cc6nonc6cc5C4)CC3)ccc21
Temperature: 55 °C

Procedure:
To a solution of 6-Piperazin-1-yl-5,6,7,8-tetrahydronaphtho[2,3-c][1,2,5]oxadiazole hydrochloride (20 mg, 0.068 mmol), 5-(2-bromoethyl)-2-benzofuran-1(3H)-one (33 mg, 0.14 mmol), and tetrabutylammonium iodide (2.5 mg, 6.8 umol) in DMF (2 mL) was added triethylamine (0.028 mL, 0.20 mmol). The mixture was heated to 55° C. for 6 hours. LC showed formation of the desired product, which was separated by mass-directed HPLC. LC-MS (IE, m/z): 419 [M+1]+. (0.21 μM)
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[N:41]1([O:50]C(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.NO>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[N:16]=2)[CH2:11][C:12]([NH:41][OH:50])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (3R)-6-cyclohexyl-3-{3-[(dimethylamino)carbonyl]-1,2,4-oxadiazol-5-yl}hexanoic acid (Preparation 11) (60 mg, 0.18 mmol) and N,N-diisopropylethylamine (30 μl, 0.18 mmol) in N—N-dimethylformamide (3 ml) was treated with O-(7-azabenzotriazol-1-yl)-N,N,N′, N′-tetramethyluronium hexafluorophosphate (100 mg, 0.27 mmol) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. Further N,N-diisopropylethylamine (90 μl, 0.52 mmol) was then added, followed by hydroxylamine hydrochloride (35 mg, 0.52 mmol) and the mixture was stirred at room temperature for 18 hours. The mixture was partitioned between ethyl acetate and pH 7 aqueous buffer. The layers were separated and the aqueous phase extracted with ethyl acetate (×2). The combined organic layers were washed sequentially with aqueous citric acid solution (5% w/v) and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:ethyl acetate (90:10) gradually changing to dichloromethane:ethyl acetate (50:50) then to dichloromethane:methanol (95:5). The residue was further purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (99:1) gradually changing to dichloromethane:methanol (95:5) to afford the title compound as an oil which crystallised on standing (35 mg).
Reaction SMILES: [ClH:1].[CH2:2]([C@@H:4]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:25])([C:21]([F:24])([F:23])[F:22])[C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)[CH3:3]>C(Cl)Cl>[ClH:1].[CH2:2]([C@H:4]1[CH2:5][NH:6][CH2:7][CH2:8][N:9]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:25])([C:17]([F:19])([F:20])[F:18])[C:21]([F:22])([F:23])[F:24])=[CH:12][CH:11]=1)[CH3:3]
Reactant: CC[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: Cl
Solvent: ClCCl
Product: CC[C@H]1CNCCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reaction time: 18 h
Yield: 87.5 %

Procedure:
HCl (4.0 M solution with 1,4-dioxane, 3.9 mL, 16 mmol) was added to a stirring solution of tert-butyl (3S)-3-ethyl-4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinecarboxylate (0.71 g, 1.6 mmol) and CH2Cl2 (7.8 mL) at room temperature. After 18 h, the reaction mixture was concentrated to give 2-(4-((2S)-2-ethyl-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol hydrochloride (0.55 g) as a brown solid. The material was used in the next step without purification.
Reaction SMILES: [Si]([O:8][C@H:9]([C:43]1[CH:52]=[CH:51][C:50]([OH:53])=[C:49]2[C:44]=1[CH:45]=[CH:46][C:47](=[O:54])[NH:48]2)[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([O:27][C:28](=[O:42])[NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:23][CH2:22]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:73]1([S:87]([OH:90])(=[O:89])=[O:88])[C:82]2[CH:81]=[CH:80][CH:79]=[C:78]([S:83]([OH:86])(=[O:85])=[O:84])[C:77]=2[CH:76]=[CH:75][CH:74]=1>C1COCC1.CO>[C:73]1([S:87]([OH:90])(=[O:89])=[O:88])[C:82]2[CH:81]=[CH:80][CH:79]=[C:78]([S:83]([OH:86])(=[O:85])=[O:84])[C:77]=2[CH:76]=[CH:75][CH:74]=1.[OH:8][C@H:9]([C:43]1[CH:52]=[CH:51][C:50]([OH:53])=[C:49]2[C:44]=1[CH:45]=[CH:46][C:47](=[O:54])[NH:48]2)[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:22][CH2:23][CH:24]([O:27][C:28](=[O:42])[NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:25][CH2:26]1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CNCCCCCCCCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)c1ccc(O)c2[nH]c(=O)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(O)c1cccc2c(S(=O)(=O)O)cccc12
Agent: [F-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1-c1ccccc1)OC1CCN(CCCCCCCCCNC[C@H](O)c2ccc(O)c3[nH]c(=O)ccc23)CC1
Temperature: 30 °C
Reaction time: 2 h
Yield: 58.2 %

Procedure:
To a 500-mL round-bottomed flask was added the crude biphenyl-2-yl-carbamic acid 1-{9-[(R)-2-(tert-butyldimethylsilanyloxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]nonyl}piperidin-4-yl ester (16 g, 18.5 mmol) and THF (100 mL) and the resulting mixture was stirred until the compound dissolved (about 10 min). A 1M solution of tetrabutylammonium fluoride (37 μL, 37 mmol) in THF was added and the resulting mixture was stirred at 40° C. under nitrogen for 6 to 7 hours (>98% conversion by HPLC). The mixture was then cooled to 30° C., and a solution of naphthalene-1,5-disulfonic acid (4.26 g, 14.8 mmol, recrystallized from acetonitrile) in methanol (100 mL) was added. The reaction mixture was then stirred at 30° C. for 3 to 4 hours and then at room temperature for 2 hours. The resulting crystalline solid was then collected by filtration, washed with methanol (20 mL) and air dried to give the title compound as an off-white crystalline solid (8 g).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[B:9](Br)(Br)[Br:10]>C(Cl)Cl>[Br:10][B:9]1[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1
Reactant: Oc1ccccc1O
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: BrB1Oc2ccccc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
Solid catechol (800 gms) was added (via a Gooch tube connected to an Erlenmeyer flask) to a 12 liter round bottom flask containing BBr3 (2 kg) in methylene chloride (3.5 liters) at -78° C. over a 6 hour period. The reaction mixture was slowly warmed to ambient temperature and stirred overnight. The solvent and excess hydrogen bromide were removed by distillation at 20 mm Hg. The residue was transferred in a minimal amount of methylene chloride to a 5 liter three neck round bottom flask and evacuated overnight at 30 mm. At this point the reaction product was very crystalline. The solid was warmed cautiously to a melt while slowly reducing the pressure. Ultimately, at a pressure of 10-15 mm an a mantle temperature of about 130° C., there was formed a colorless distillate at a head temperature of about 95° C. The liquid crystallized rapidly on cooling. The solid was transferred to Teflon bottles to yield 1.32 kg (92% yield) of 2 -bromo-1,3,2 benzodioxaborole, a colorless, fuming, pourable solid.