Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH2:4]O)=O.[CH3:6][C:7]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:8]=1[NH2:9].[C:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])#[N:17]>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[NH2:17][C:16]1[N:9]([C:8]2[C:10]([CH3:15])=[CH:11][C:12]([CH3:14])=[CH:13][C:7]=2[CH3:6])[C:2]([CH3:4])=[CH:1][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: CC(=O)CO
Reactant: CCOC(=O)CC#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)c1cc(C)n(-c2c(C)cc(C)cc2C)c1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.7 %

Procedure:
A solution of acetol (1) (20 mL, 0.26 mol), 2,4,6-trimethylaniline (2) (36.5 mL, 0.260 mol), and 4-toluenesulfonic acid monohydrate (0.21 g) were refluxed in benzene (115 mL) using a Dean-Stark trap to remove water. After 2 hours, ethyl cyanoacetate (27.7 mL, 0.26 mol) was added and heating was continued for 14 hours. The mixture was cooled to room temperature, concentrated, and the residue chromatographed (elution with 15% ethyl acetate in hexanes) to afford 21.4 g (29%) of compound (11) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]([CH3:8])([CH3:7])[C:3]([CH3:6])([OH:5])[CH3:4].[Cl:9][C:10]1[C:17]([C:18]#[C:19][Si](C)(C)C)=[C:16](F)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13].C([O-])([O-])=O.[K+].[K+].CN1C(=O)CCC1>O.CCOC(C)=O>[Cl:9][C:10]1[C:11]([C:12]#[N:13])=[CH:14][CH:15]=[C:16]2[C:17]=1[CH:18]=[CH:19][N:1]2[C:2]([CH3:8])([C:3]([OH:5])([CH3:6])[CH3:4])[CH3:7]
Reactant: C[Si](C)(C)C#Cc1c(F)ccc(C#N)c1Cl
Reactant: CC(C)(N)C(C)(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(O)C(C)(C)n1ccc2c(Cl)c(C#N)ccc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 5.3 %

Procedure:
An oven-dried vial was charged with 3-amino-2,3-dimethylbutan-2-ol (0.063 g, 0.539 mmol), 2-chloro-4-fluoro-3-((trimethylsilyl)ethynyl)benzonitrile (Example 32B) (0.113 g, 0.449 mmol), and K2CO3 (0.137 g, 0.988 mmol) and sealed with a rubber septum. Anhyd NMP (3 mL) was added via syringe and the mixture was stirred in a heating block at 60° C. under N2. After 1 h, the vial was sealed with a PTFE-faced crimp top and subjected to microwave heating; 1 h at 140° C. followed by 45 min at 160° C. (with air cooling). The mixture was poured into water/EtOAc and the whole was filtered through a pad of Celite. Layers of the filtrate were separated and the aqueous layer was extracted with EtOAc (×2). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (C18 stationary phase, MeCN/water gradient with 0.1% TFA additive) affording 4-chloro-1-(3-hydroxy-2,3-dimethylbutan-2-yl)-1H-indole-5-carbonitrile (0.0066 g, 5% yield) as a tan solid (ca. 85% purity): 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J=9.0 Hz, 1H), 7.49 (d, J=3.5 Hz, 1H), 7.32 (d, J=8.9 Hz, 1H), 6.71 (d, J=3.4 Hz, 1H), 1.87 (s, 6H), 1.20 (s, 6H); MS (LCMS ES+) m/z 277 ([M+H]+, 65%), 318 ({[M+H]+MeCN}+, 100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[CH:15]1([CH:18]=[CH:19][C:20]#[N:21])[CH2:17][CH2:16]1.C1CCN2C(=NCCC2)CC1>CC#N>[CH:15]1([CH:18]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:19][C:20]#[N:21])[CH2:17][CH2:16]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: N#CC=CC1CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC1(C)OB(c2cnn(C(CC#N)C3CC3)c2)OC1(C)C
Temperature: 40 °C
Reaction time: 72 h
Yield: 68.6 %

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.44 g, 12.6 mmol), 3-cyclopropylacrylonitrile (Preparation B; 2.34 g, 25.1 mmol) (as a mixture of isomers) and DBU (1.88 mL, 12.6 mmol) were suspended in MeCN (10 mL) and stirred at 40° C. for 3 days. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 25-35% EtOAc/Hexanes) to furnish 3-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile (2.48 g, 8.64 mmol, 68.8% yield). MS (apci) m/z=288.2 (M+H).
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:28])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH3:27].[F:29][C:30]([F:54])([C:50]([F:53])([F:52])[F:51])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]COS(C1C=CC(C)=CC=1)(=O)=O.[C:55](=O)(O)[O-].[Na+]>CN(C)C=O>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:28])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:55])[CH2:27][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][C:30]([F:29])([F:54])[C:50]([F:51])([F:52])[F:53]
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCCCC(F)(F)C(F)(F)F)cc1
Reactant: O=C([O-])O
Reactant: CNCCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCCCCCCCC(F)(F)C(F)(F)F)CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F

Procedure:
A solution of 260 mg of 11β-fluoro-3-hydroxy-7α-[5-(methyl-amino)-pentyl]-estra-1,3,5(10)-trien-17-one in 3 ml of dimethylformamide is stirred with 180 mg of 9,9,10,10,10-pentafluorodecyltosylate for 1 hour at a bath temperature of 100° C. Then, it is added to semi-saturated sodium bicarbonate solution, extracted three times with methylene chloride, dried on magnesium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane/methanol/triethylamine. 92 mg of 11β-fluoro-3-hydroxy-7α-{5-[methyl-(9,9,10,10,10-pentafluoro-decyl)-amino]-pentyl}-estra-1,3,5(10)-trien-17-one is obtained as a foam, [α]D=+48° (c=1.0 in chloroform).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][N:10]=[CH:11][CH:12]=2)[S:7]1.C(N(CC)CC)C.[N+:23]([C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)([O-:25])=[O:24]>O1CCCC1>[N+:23]([C:26]1[CH:27]=[CH:28][C:29]([S:32]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:14](=[O:15])[C:13]3[C:8](=[CH:9][N:10]=[CH:11][CH:12]=3)[S:7]2)(=[O:34])=[O:33])=[CH:30][CH:31]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: O=c1c2ccncc2sn1CCCCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=c1c2ccncc2sn1CCCCOS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 4 h

Procedure:
To a stirred solution of 0.73 g of 2-(4-hydroxybutyl)isothiazolo[5,4-c]pyridin-3(2H)-one and 0.8 mL of triethylamine in 50 mL of dry tetrahydrofuran at 0° C. was added 0.63 g of technical grade 4-nitrobenzenesulfonyl chloride. After 4 h, the solution was filtered and concentrated to dryness under reduced pressure. The residue was dissolved in 100 mL of ethyl acetate, washed with 10 mL of saturated sodium carbonate and dried over MgSO4. Concentration under reduced pressure gave 1.4 g of crude 2-(4-(4-nitrobenzenesulfonyloxy)butyl)-isothiazolo[5,4-c]pyridin-3(2H)-one as an oil. The crude product was a mixture of 4-nitrobenzenesulfonate contaminated with a small amount of chloride by NMR, and was used in the next step without further purification.
Reaction SMILES: Cl[CH:2]([CH3:15])[C:3]([NH:5][C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][C:9](=[O:11])[NH2:10])=[O:4].[NH3:16]>>[NH2:5][C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][C:9](=[O:11])[NH2:10].[NH2:16][C@H:2]([C:3]([NH:5][C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][C:9](=[O:11])[NH2:10])=[O:4])[CH3:15]
Reactant: CC(Cl)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Reactant: N
Product: C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Product: NC(=O)CC[C@H](N)C(=O)O

Procedure:
Alanylglutamine is prepared according to Chinese Patent CN1680428A. Wherein, N-α-chloropropionyl)-L-glutamine is synthesized first. Then, 0.12 g of the N-(α-chloropropionyl)-L-glutamine crystals containing two diastereomeric isomers and 300 mL of 28% aqueous ammonia are mixed in a reaction vessel under room temperature. The reaction is carried out under 60° C. temperature and 2 kg/cm2 pressure. L-Alanyl-L-glutamine crude product is obtained after workup procedures. TLC shows an Rf value of 0.14, with acetate:n-butanol:water (1:4:1) eluent and ninhydrin stain. The above L-alanyl-L-glutamine crude product is dissolved in water, charged with activated carbon, and stirred under room temperature. Then the activated carbon is filtered out, mother crystals are added into the solution, and the system is settled for a while.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](Br)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2.[C:13](=[O:16])([O-])[O-].[K+].[K+].O>C(COC)OC>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]2[CH:2]=[CH:3][CH:4]=[C:13]([OH:16])[CH:9]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2
Reactant: Nc1ccc(Br)c2c1C(=O)NC2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Nc1ccc(-c2cccc(O)c2)c2c1C(=O)NC2
Yield: 176.3 %

Procedure:
In a similar manner to Step 1 of Example 152, 7-amino-4-bromoisoindolinone (150 mg, 0.661 mmol) was dissolved in dimethoxyethane (10.5 mL), and the solution was treated with 3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenol (291 mg, 1.32 mmol), [bis(diphenylphosphino)ferrocene]dichloropalladium (43 mg, 0.053 mmol), potassium carbonate (455 mg, 3.31 mmol) and water (0.24 mL), followed by purification by slurry using chloroform to obtain 7-amino-4-(3-hydroxyphenyl)isoindolinone (140 mg, yield 88%).
Reaction SMILES: [CH2:1]([C@H:4]1[N:11]([S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)(=[O:14])=[O:13])[CH2:10][C:9]2[CH:25]=[CH:26][CH:27]=[CH:28][C:8]=2[CH2:7][O:6][CH2:5]1)[CH:2]=[CH2:3].[CH2:29]([Zn]CC)C.ICI.[Cl-].[NH4+]>C1COCC1>[CH:2]1([CH2:1][C@H:4]2[N:11]([S:12]([C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:24]=3[N:23]=[CH:22][CH:21]=[CH:20]4)(=[O:14])=[O:13])[CH2:10][C:9]3[CH:25]=[CH:26][CH:27]=[CH:28][C:8]=3[CH2:7][O:6][CH2:5]2)[CH2:29][CH2:3]1
Reactant: C=CC[C@@H]1COCc2ccccc2CN1S(=O)(=O)c1cccc2cccnc12
Reactant: CC[Zn]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ICI
Product: O=S(=O)(c1cccc2cccnc12)N1Cc2ccccc2COC[C@H]1CC1CC1
Temperature: 0 °C
Reaction time: 6 h
Yield: 31 %

Procedure:
To a stirred solution of compound 18 (100 mg, 0.25 mmol) in dry THF (5 mL) was added diethyl zinc (1M solution in hexane, 2.5 mL) at 0° C. under nitrogen atmosphere followed by diiodomethane (667 mg, 2.5 mmol). The reaction was stirred at 0° C. for 6 h and poured over cold aqueous solution of ammonium chloride. The organic layer was separated and the aqueous layer extracted repeatedly with EA. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by Prep-TLC to afford the compound 20 (32 mg, 31% yield). 1H NMR (500 MHz, CDCl3) δ 8.94 (m, 1H), 8.47 (d, J=7.5 Hz, 1H), 8.13 (d, J=8.0 Hz, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.43 (dd, J=8.0 Hz, 4.0 Hz 1H), 7.17 (d, J=7.5 Hz, 1H), 6.98 (t, J=7.5 Hz, 1H), 6.89 (m, 1H), 6.80 (d, J=7.5 Hz, 1H), 5.07 (d, J=15.5 Hz, 1H), 4.95 (d, J=15.0 Hz, 1H), 4.86 (d, J=15.5 Hz, 1H), 4.60 (d, J=15.0 Hz, 1H), 4.49 (m, 1H), 4.14 (d, J=12.0 Hz, 1H), 3.75 (d, J=12.0 Hz, 1H), 1.71 (m, 1H), 1.10 (m, 1H), 0.63 (m, 1H), 0.33 (m, 2H), −0.11 (m, 2H). MS (ESI+) m/z: 409 [M+H]+. LCMS (m/z): 409.2 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C:5]1[CH:10]=[C:9]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:8]=[C:7]([NH2:34])[CH:6]=1)[CH3:2].N1C=CC=CC=1.[CH3:42][S:43](Cl)(=[O:45])=[O:44].O>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([O:3][C:4](=[O:35])[C:5]1[CH:10]=[C:9]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:8]=[C:7]([NH:34][S:43]([CH3:42])(=[O:45])=[O:44])[CH:6]=1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1cc(N)cc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccccc3)CCC2)c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(NS(C)(=O)=O)cc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccccc3)CCC2)c1
Yield: 81.9 %

Procedure:
5-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl)-3-aminobenzoic acid ethyl ester (60 mg, 0.12 mmol), pyridine (11 μL, 0.137 mmol), methane sulphonyl chloride (11 μL, 0.137 mmol), and a catalytic amount of DMAP in 2 mL of dichloromethane were stirred at room temperature for 2 hrs. The reaction mixture was poured into water and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried (MgSO4), filtered and concentrated. Purification was carried out on a SPE using iso-hexane containing a gradient of ethyl acetate (5–30%) to give the required product as yellow oil (55 mg, 78%). 1H NMR (CDCl3):1.32 (3H,t,J=7.1), 2.06–2.13 (2H,m), 2.60(3H,s), 2.88 (2H,t,J=7.4), 2.92–296(2H,m), 4.31 (2H,q,J=7.1), 5.11 (2H,s), 6.42 (1H,s), 7.04 (1H,d,J=8.6), 7.11 (1H,s), 7.23–7.30 (5H,m), 7.33(1H,d), 7.54 (1H,s), 7.66 (1H,s). LC/MS[MH−]=558 Rt=4.11.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1B(O)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br.Br[C:30]1[CH:35]=[CH:34][N:33]=[N:32][CH:31]=1>O1CCOCC1.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[C:30]1[CH:35]=[CH:34][N:33]=[N:32][CH:31]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccnnc1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1OCc1ccccc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)c1ccc(OCc2ccccc2)c(-c2ccnnc2)c1
Reaction time: 3 h

Procedure:
([2-(benzyloxy)-5-(trifluoromethyl)phenyl]boronic acid (3.72 g, 0.0126 mol) and caesium carbonate (8.9 g, 0.0273 mol) were suspended in 1,4 dioxane (40.0 mL) and water (20.0 mL). The reaction was degassed twice before being brought to 80° C. under nitrogen. Then 4-bromopyridazine hydrobromide (Preparation see above, 2.52 g, 0.0105 mol) and palladium tetrakistriphenylphosphine (0.62 g, 0.000537 mol) were added to the reaction and it was stirred for three hours. The reaction was concentrated in vacuo to 20.0 mL, and partitioned between ethyl acetate (70.0 mL) and saturated aqueous brine (50.0 mL). The two layers were filtered over Arbocel™ to remove a fine black solid. Then the organic layer was washed with more saturated aqueous brine (2×50.0 mL) and it was dried over sodium sulphate. The solvents were concentrated in vacuo and crude was purified using ISCO™ (using a gradient of 0-50% ethyl acetate in heptane, 80 g SiO2) to afford the title compound as a light orange solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH:15]3[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]3)[CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1.C1COCC1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=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.O.C(O)C>[C:23]1([C:2]2[N:7]=[C:6]([CH2:8][N:9]3[CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11][CH2:10]3)[CH:5]=[CH:4][CH:3]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1cccc(CN2CCN3CCC2CC3)n1
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: C1CCOC1
Solvent: O
Solvent: CCO
Product: c1ccc(-c2cccc(CN3CCN4CCC3CC4)n2)cc1
Yield: 27.3 %

Procedure:
To a stirred solution of 4-(6-bromo-pyridin-2-ylmethyl)-1,4-diaza-bicyclo[3.2.2]nonane (17.0 mg, 0.06 mmol) in a solvent mixture of THF, ethanol, and water (6.0 mL of 1:1:1) was added phenylboronic acid (18 mg, 0.15 mmol), potassium carbonate (70 mg), and a catalytic amount of tetrakis(triphenylphosphine)palladium(0). The mixture was heated at reflux temperature for 3 hours, cooled, and concentrated to near dryness. The residue was triturated with chloroform (3×) and the crude product in chloroform subjected silica gel chromatography eluting with a chloroform (ammoniated) to 5% methanollchloroform gradient to give the title compound as an off-white solid (4.8 mg). MS (ES+) 294 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[C:14]1([CH2:20][CH2:21][CH2:22]O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:14]1([CH2:20][CH2:21][CH2:22][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: OCCCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(OCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 3-(4-hydroxyphenyl)propanoate (2.50 g) and 3-phenylpropan-1-ol (2.8 mL) in tetrahydrofuran (70 mL), triphenylphosphine (5.46 g) was added at room temperature. Next, diethyl azodicarboxylate (9.4 mL, 40% toluene solution) was added dropwise thereto, followed by stirring at room temperature for 2 hours. Then, the reaction mixture was concentrated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1 to 5:1) to give the title compound (3.02 g) having the following physical properties.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:15][C:14]=3[N:25]([CH3:34])[S:26]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)(=[O:28])=[O:27])=[N:8][CH2:7]1)C.[OH-].[Na+].O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[CH3:34][N:25]([S:26]([C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)(=[O:28])=[O:27])[C:14]1[CH:15]=[C:16]([O:20][C:21]([F:22])([F:24])[F:23])[CH:17]=[C:18]2[C:13]=1[NH:12][C:11]([C:9]1[S:10][CH:6]([CH2:5][C:4]([OH:35])=[O:3])[CH2:7][N:8]=1)=[CH:19]2
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(OC(F)(F)F)cc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(c1cc(OC(F)(F)F)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 94.9 %

Procedure:
A mixture of ethyl{2-[7-[methyl(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (300 mg), 1N aqueous sodium hydroxide solution (5 mL), tetrahydrofuran (5 mL) and ethanol (5 mL) was stirred at room temperature for 15 hr. The reaction mixture was acidified with aqueous citric acid solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was crystallized from ethyl acetate-hexane to give the title compound (270 mg, yield 93%) as pale-yellow crystals. The crystals were purified by preparative HPLC, and recrystallized from ethyl acetate-hexane to give pale-yellow prism crystals. melting point 225-227° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9](=[O:11])[CH3:10])[CH:2]=1.[CH3:12][I:13]>C(Cl)Cl>[I-:13].[C:9]([NH:8][CH2:7][C:3]1[CH:2]=[N+:1]([CH3:12])[CH:6]=[CH:5][CH:4]=1)(=[O:11])[CH3:10]
Reactant: CI
Reactant: CC(=O)NCc1cccnc1
Solvent: ClCCl
Product: CC(=O)NCc1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of N-(pyridin-3-ylmethyl)acetamide (13.89 g, 92 mmol) in DCM at 0° C. was added methyl iodide (8.10 mL, 129 mmol). The cooling bath was removed after 10 min and the solution was stirred at rt for 19 h, whereupon it was concentrated in vacuo and used as crude in step 3. LCMS: Rt=0.18 min, m/z=164.9 (M+) Method 2m_acidic. 1H NMR (400 MHz, DMSO-d6) δ 8.91-8.87 (m, 2H) 8.58 (brs, 1H) 8.42 (d, J=8.0 Hz, 1H) 8.09 (t, J=7.0 Hz, 1H) 4.43 (d, J=5.9 Hz, 2H) 4.35 (s, 3H) 1.92 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.ClC1N=CN=C(C(NC2C=CC(O)=CC=2)=O)C=1.[NH2:28][C:29]1[C:30]([CH3:35])=[CH:31][CH:32]=[CH:33][CH:34]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])=[O:9])[CH:3]=1
Reactant: Cc1ccccc1N
Reactant: O=C(Cl)c1cc(Cl)ncn1
Agent: O=C(Nc1ccc(O)cc1)c1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1NC(=O)c1cc(Cl)ncn1

Procedure:
A cooled (0° C.) solution of 6-chloropyrimidine-4-carbonyl chloride (26.76 g; 151 mmol), obtained as described above for Intermediate 7 step 1, in anhydrous DCM (270 ml) was treated dropwise over 25 minutes with a solution of o-toluidine (13.6 ml; 126.0 mmol) and DIEA (43.4 ml; 252 mmol) in anhydrous DCM (100 mL). At the end of addition, the reaction mixture was washed with water then brine, dried over MgSO4, filtered and dried under vacuum to afford the title compound used without further purification as a brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:16][C:17]2[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=2)([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.CS(O[CH2:31][CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[C:36]([O:35][C:34]([NH:33][CH2:32][CH2:31][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:16][C:17]2[CH:18]=[CH:19][C:20]([CH:23]([CH3:24])[CH3:25])=[CH:21][CH:22]=2)([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1)=[O:40])([CH3:39])([CH3:38])[CH3:37]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C(C)C)cc1
Reactant: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(C)(Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1)Oc1ccc(C(C)C)cc1
Yield: 90.6 %

Procedure:
In a similar manner to that described in Reference example 25, a reaction was carried out using ethyl 3-(4-hydroxyphenyl)-2-(4-isopropylphenoxy)-2-methylpropionate (4.85 g), which is the product of Reference example 9(b), t-butyl 2-methanesulfonyloxy-ethylcarbamate (8.47 g) and potassium carbonate (9.78 g) and the reaction mixture was treated to afford the title compound (6.23 g) as a colorless oil.
Reaction SMILES: C([Sn](CCCC)CCCC)CCC.[Cl:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]2[CH:21]=[C:22]([C:24]3S[CH:26]=[CH:27][N:28]=3)[S:23][C:16]=12.Br[C:30]1[N:31](C)C=CN=1>>[Cl:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]2[CH:21]=[C:22]([C:24]3[N:31]([CH3:30])[CH:26]=[CH:27][N:28]=3)[S:23][C:16]=12
Reactant: Cn1ccnc1Br
Reactant: Clc1ccnc2cc(-c3nccs3)sc12
Agent: CCCC[Sn](CCCC)CCCC
Product: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Yield: 95 %

Procedure:
Starting from tributyltin compound 98 (scheme 19) and following the procedure described above for the synthesis of compound 10 (scheme 2, step 2, example 12) but replacing 2-bromothiazole with 2-bromo-1-methyl-1H-imidazole, title compound 214 was obtained in 95% yield. MS (m/z) 250.1 (100%), 252.1 (37%), (M+H).
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[Na+].Cl.[NH2:7][OH:8].[Cl:9][CH:10]=[C:11]1[CH:17]=[CH:16][C:15]2[CH:18]=[C:19]([CH:22]=O)[CH:20]=[CH:21]C=2O[CH2:12]1>CO>[Cl:9][CH:10]=[C:11]1[CH:17]=[CH:16][C:15]2[CH:18]=[C:19]([C:20](=[N:7][OH:8])[CH3:21])[CH:22]=[CH:2][C:1]=2[O:4][CH2:12]1
Reactant: NO
Reactant: CC(=O)[O-]
Reactant: O=Cc1ccc2c(c1)C=CC(=CCl)CO2
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(=NO)c1ccc2c(c1)C=CC(=CCl)CO2
Reaction time: 24 h
Yield: 103.1 %

Procedure:
12.3 mg (0.15 mmol) of sodium acetate and then 10.4 mg (0.15 mmol) of hydroxylamine hydrochloride are added at ambient temperature to 30 mg (0.136 mmol) of 3-(chloromethylene)-2,3-dihydro-1-benzoxepin-7-carbaldehyde, prepared according to example 72, in solution in 2 ml of methanol. The solution is stirred for 24 hours and is then hydrolyzed. A conventional treatment makes it possible to obtain 35 mg (100%) of 1-[3-(chloromethylene)-2,3-dihydro-1-benzoxepin-7-yl]ethanone oxime in the solid form; 1H NMR: 7.9–8.3 (broad s, OH), 8.10 (8.05) (s, 1H), 7.35–7.45 (m, 2H), 7.03 (7.00) (d, J=8.4 Hz, 1H), 6.84 (d, J=11.7 Hz, 1H), 6.35 (s, 3H), 4.88 (4.57)(s, 2H).