Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH:3]=O.[CH3:5][O:6][C:7](=[O:25])[C:8]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:22])=[C:12]([Cl:23])[C:11]([NH2:24])=[N:10][CH:9]=1>CN(C=O)C.O>[CH3:5][O:6][C:7]([C:8]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:22])=[C:12]([Cl:23])[C:11]2[N:10]([CH:2]=[CH:3][N:24]=2)[CH:9]=1)=[O:25]
Reactant: O=CCCl
Reactant: COC(=O)c1cnc(N)c(Cl)c1Nc1ccc(Br)cc1Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cn2ccnc2c(Cl)c1Nc1ccc(Br)cc1Cl
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Chloroacetaldehyde (50% aqueous solution, 0.70 mL, 5.7 mmol) was added to a suspension of 6-amino-4-(4-bromo-2-chlorophenylamino)-5-chloronicotinic acid methyl ester (28) in DMF (7 mL) contained in a sealed tube. The reaction mixture was heated at 80° C. for four hours and then allowed to cool to room temperature and stir overnight. The dark brown solution was diluted with water (70 mL) the resulting light brown precipitate was collected by filtration and washed with water. The solids were dissolved into THF. Two volumes of ethyl acetate were added and the organic solution washed with brine, dried over NaSO4, filtered, and concentrated in vacuo to provide a brown solid. The aqueous filtrate was extracted with ethyl acetate and the organic extracts were dried over NaSO4, filtered, and concentrated in vacuo. This material was combined with the previously isolated brown solid and the combined material subjected to column chromatography (dichloromethane, followed by 20:1 dichloromethane/methanol). The desired product (29) was isolated as a light yellow solid (0.752 g, 64%). MS (APCI+) m/z 414, 416, 418 (M+; Cl, Br pattern) detected.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([O:33][C:34](=[O:37])CBr)[C:27]1C=CC=CC=1>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:25])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:34]([O:33][CH2:26][CH3:27])=[O:37])=[CH:12][CH:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: O=C(OCc1ccccc1)c1ccc(CNCc2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)N(Cc1ccccc1)Cc1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 0 °C

Procedure:
A solution of 4-(N-benzylaminomethyl)benzoic acid benzyl ester (5.21 g) and bromoacetic acid benzyl ester (1.7 ml) in DMF (10 ml) was stirred for two hours at 80° C. and ice water was added thereto. The reaction solution was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, water and a saturated aqueous solution of sodium chloride, successively. The organic layer was dried over and evaporated. The residue was purified by silica gel column chromatography to obtain the title compound (2.26 g).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:32][CH2:33][CH2:34][OH:35].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:29])([F:30])[F:31])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:32][CH2:33][CH2:34][OH:35])=[O:5]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NCCO)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 21.7 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 130 mg, 0.3 mmol) was dissolved in DMF (2 mL) and cooled to 0° C. prior to the addition of 2-aminoethanol (27.6 mg, 0.452 mmol), 4-methylmorpholine (0.133 mL, 1.206 mmol), and HATU (149 mg, 0.392 mmol). This was stirred overnight and was then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 15 mL/min, 220 nM, product retention=33.8 min) to give (R/S)-2-hydroxy-N-(2-hydroxyethyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (34 mg, 0.065 mmol, 21.3% yield): LCMS [M+H]+=475.1; 1H NMR (400 MHz, methanol-d4) δ ppm 8.16 (2 H, dd, J=8.35, 4.39 Hz), 7.64-7.77 (4 H, m), 7.47-7.64 (3 H, m), 5.10-5.21 (1 H, m), 4.46 (2 H, t, J=5.49 Hz), 3.55-3.69 (2 H, m), 3.37 (1 H, m). HPLC Peak RT=8.6 min (Analytical Method A).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[F:18])=[N:5]1.[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[S:28][CH:29]=[C:30]([C:32](O)=[O:33])[N:31]=2)[CH2:22][CH2:21]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:17][C:11]1[C:10]([F:18])=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:32]([C:30]3[N:31]=[C:27]([CH2:26][N:23]4[CH2:22][CH2:21][O:20][CH2:25][CH2:24]4)[S:28][CH:29]=3)=[O:33])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=C(O)c1csc(CN2CCOCC2)n1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2F)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2F)n1)NC(=O)c1csc(CN2CCOCC2)n1

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-fluorobenzonitrile (0.3 g, 1.07 mmol), 2-(morpholinomethyl)-thiazole-4-carboxylic acid (0.29 g, 1.29 mmol), HOBt (0.22 g, 1.61 mmol), DIPEA (0.56 mL, 3.23 mmol) and EDCI (0.31 g, 1.61 mmol) in 10 mL DMF as solvent using the method of Example 34(d). Yield 0.27 g. 1H NMR (400 MHz; d6-DMSO): 1.13 (d, 3H), 3.61 (m, 4H), 3.84 (d, 2H), 4.39 (m, 3H), 6.78 (dd, 1H), 7.84 (dd, 1H), 7.90 (d, 1H), 8.06 (dd, 1H), 8.15 (s, 1H), 8.45 (d, 1H).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:5]([O:15][C:16]2[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[O:25])=[CH:18][CH:17]=2)[C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13]C)=[CH:8][CH:7]=2)[CH3:2].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([OH:13])=[CH:10]2)=[C:5]([O:15][C:16]2[CH:17]=[CH:18][C:19](/[CH:22]=[CH:23]/[C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[O:25])=[CH:20][CH:21]=2)[C:4]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:2]
Reactant: CCc1cc2cc(OC)ccc2c(Oc2ccc(/C=C/C(=O)N3CCN(C)CC3)cc2)c1-c1ccccc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1cc2cc(O)ccc2c(Oc2ccc(/C=C/C(=O)N3CCN(C)CC3)cc2)c1-c1ccccc1
Reaction time: 6 h
Yield: 52.5 %

Procedure:
To a solution of 1-[(2E)-3-(4-{[3-ethyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}phenyl)-2-propenoyl]-4-methylpiperazine (61) (83 mg, 0.17 mmol) in reagent grade CH2Cl2 (8 mL) at −10° C. was added BBr3 (97 μL, 1.03 mmol) dropwise. The mixture was then stirred at 0° C. to 5° C. for 6 h, poured into saturated aqueous NaHCO3 (30 mL) and extracted with CH2Cl2. The combined extract was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a brown solid. The crude product was triturated with hot hexanes (containing small amount of CH2Cl2 and MeOH) to give 44 mg (55%) of the title compound (63) as an off-white solid. mp 195-196° C. 1H NMR (400 MHz, CH3OH-d4): δ 1.07 (t, J=7.5 Hz, 3H), 2.31 (s, 3H), 2.47 (br s, 4H), 2.54 (q, J=7.5 Hz, 2H), 3.70 (br s, 4H), 6.54 (d, J=8.8 Hz, 2H), 6.91 (d, J=15.4 Hz, 1H), 6.96 (dd, J1=9.1 Hz, J2=2.4 Hz, 1H), 7.10-7.17 (m, 3H), 7.18-7.28 (m, 3H), 7.37 (d, J=8.6 Hz, 2H), 7.44 (d, J=15.4 Hz, 1H), 7.52 (s, 1H), 7.60 (d, J=9.1 Hz, 1H). LCMS (ESI): m/z 493 (M+H)+, m/z 491 (M−H)−. HRMS (EI) Calc for C32H32 N2O3: 493.2491 (M+•). Found: 493.2500.
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=[CH:3]1.[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[CH3:10][C:4]1[CH:5]([Br:11])[C:6]([CH3:8])([CH3:7])[CH2:9][C:2](=[O:1])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1=CC(=O)CC(C)(C)C1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC1=CC(=O)CC(C)(C)C1Br

Procedure:
A mixture of isophorone (13.82 g; 0.1 Mole) and N-bromo-succinimide (17.80 g; 0.1 Mole) in the presence of traces of α,α'-azodiisobutyronitrile was refluxed in 500 ml of CCl4 during 15 minutes. 500 ml of petrol-ether (30°-50° C.) were then added to the cool reaction mixture and the succinimide thus precipitated was filtered off. By evaporating the volatile components of the clear filtrate, crude 3,5,5-trimethyl-4-bromo-cyclohex-2-en-1-one was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[N:18]O)[CH2:10][CH2:9]1.[OH2:20]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[NH:18][C:11](=[O:20])[CH2:10][CH2:9]1
Reactant: ON=C1CCC(c2ccccc2F)c2ccccc21
Reactant: O
Product: O=C1CCC(c2ccccc2F)c2ccccc2N1
Reaction time: 0.5 h

Procedure:
26 g of 4-(2-fluorophenyl)-1-tetralone oxime are added to 130 g of polyphosphoric acid pre-heated to 125°. The solution obtained is stirred at 125° for 30 minutes, cooled, mixed with ice and water and extracted with chloroform. After evaporation of the organic phase, the residue is crystallized from ethanol. There is obtained 5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one of melting point 210°-212°.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6]NC(C)C)[C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]1=2.[N+:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])([O-:17])=[O:16]>C1(C)C(C)=CC=CC=1>[CH2:22]([O:21][C:19](=[O:20])[CH:18]([N+:15]([O-:17])=[O:16])[CH2:6][C:4]1[C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=2[S:1][CH:5]=1)[CH3:23]
Reactant: CC(C)NCc1csc2ccccc12
Reactant: CCOC(=O)C[N+](=O)[O-]
Solvent: Cc1ccccc1C
Product: CCOC(=O)C(Cc1csc2ccccc12)[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 5 h
Yield: 74.8 %

Procedure:
In 50 ml of dry xylene were dissolved 10.97 g of (benzo[b]thiophen-3-ylmethyl)isopropylamine and 13.3 g of ethyl nitroacetate and the temperature of the solution was raised to 100° C. with stirring under nitrogen gas stream. After 5 hours. insoluble matter was filtered off, the solvent was distilled off under reduced pressure from the filtrate, and the residue was dissolved in 500 ml of ethyl acetate. The solution was washed thrice with 100 ml of an aqueous 5% citric acid solution, thrice with 100 ml of an aqueous 5% sodium hydrogencarbonate solution, and then twice with 100 ml of a saturated aqueous sodium chloride solution and after drying with sodium sulfate, ethyl acetate was distilled off under reduced pressure from the solution. After removing excess ethyl nitroacetate by means of a vacuum pump, the residue was subjected to silica gel column chromatography to provide 11.17 g (yield of 80%) of 3-(benzo[b]thiophen-3-yl)-2-nitropropionic acid ethyl ester.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([C:21]([OH:23])=[O:22])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:30])[CH:17]=4)[C:12]3=[O:31])=[CH:9][C:4]=2[O:3][CH2:2]1.[N:32]1[CH:37]=[CH:36][C:35]([CH2:38]O)=[CH:34][CH:33]=1>>[N:32]1[CH:37]=[CH:36][C:35]([CH2:38][O:22][C:21]([C:20]2[N:11]([CH2:10][C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)[C:12](=[O:31])[C:13]3[C:18]([C:19]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:17][C:16]([Br:30])=[CH:15][CH:14]=3)=[O:23])=[CH:34][CH:33]=1
Reactant: OCc1ccncc1
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Product: O=C(OCc1ccncc1)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2

Procedure:
The present compound was synthesized by a method similar to that in Example 200 and using 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (300 mg) and 4-pyridinemethanol. Colorless crystals (246 mg).
Reaction SMILES: [CH2:1]([N:8]([CH2:11][CH:12]1[O:17][C:16]2[CH:18]=[C:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:20]=[CH:21][C:15]=2[CH2:14][O:13]1)CC)[C:2]1C=CC=CC=1>[Pd].CCO>[CH3:25][S:22]([C:19]1[CH:20]=[CH:21][C:15]2[CH2:14][O:13][CH:12]([CH2:11][NH:8][CH2:1][CH3:2])[O:17][C:16]=2[CH:18]=1)(=[O:23])=[O:24]
Reactant: CCN(Cc1ccccc1)CC1OCc2ccc(S(C)(=O)=O)cc2O1
Agent: [Pd]
Solvent: CCO
Product: CCNCC1OCc2ccc(S(C)(=O)=O)cc2O1
Yield: 73.1 %

Procedure:
Preparation according to Example 10. (+)-N-benzyl-N-{[7-(methylsulfonyl)-4H-1,3-benzodioxin-2-yl]methyl}ethanamine (0.42 g, 1.16 mmol), palladium on carbon (10%, 30 mg) and EtOH (10 ml) was hydrogenated at 50 psi for 7 h. Purification afforded the pure title compound (0.23 g, 73%, >95% e.e). The amine was converted into the hydrochloric acid salt and crystallized from EtOH/MeOH/DEE. M.p. 218° C. [α]DMeOH=+77°. 1H-NMR (400 MHz, CDCl3): δ 7.51 (1H, dd, J1 7.6 Hz, J2 1.6 Hz), δ 7.47 (1H, d, J 1.6 Hz), δ 7.19 (1H, d, J 7.6 Hz), δ 5.21 (1H, t, J 5.2 Hz), δ 5.01 (2H, dd, J1 49 Hz, J2 15 Hz), δ 3.05 (3H, s), δ 2.78 (2H, m), δ 1.45 (1H, s), δ 1.80 (3H, t, J 7.2 Hz).
Reaction SMILES: C([O:5][C:6](=[O:25])[CH2:7][CH2:8][C:9]([C:22](=[O:24])[CH3:23])([C:19](=[O:21])[CH3:20])[CH2:10][CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])(C)(C)C.Cl>C(O)(C)(C)C.O>[C:22]([C:9]([C:19](=[O:21])[CH3:20])([CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH2:8][CH2:7][C:6]([OH:25])=[O:5])(=[O:24])[CH3:23]
Reactant: CC(=O)C(CCC(=O)OC(C)(C)C)(CCC(=O)OC(C)(C)C)C(C)=O
Agent: Cl
Solvent: CC(C)(C)O
Solvent: O
Product: CC(=O)C(CCC(=O)O)(CCC(=O)O)C(C)=O
Yield: 69 %

Procedure:
4,4-Diacetyl-heptanedioic acid di-tert-butyl ester was hydrolyzed at 95° C. over 5 hours using a mixture of tert-butanol and water as solvent and 11 weight-% hydrochloric acid. The solvent was removed and the obtained crude product was recrystallized from a mixture of acetone and petroleum ether (1:1) to yield 4,4-diacetyl-heptanedioic acid as white crystals at a yield of 69%. (melting point: 176° C.; purity 94%; colorless).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[O:5][C:6]1[C:7]([N+:22]([O-:24])=[O:23])=[C:8]([CH:18]=[C:19]([F:21])[CH:20]=1)[NH:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=1[F:17].NC1C=C(C=CC=1)OC1C=C(F)C([N+]([O-])=O)=C(C=1)NC1C=CC(I)=CC=1F.[CH2:55]([S:57](Cl)(=[O:59])=[O:58])[CH3:56].FC1C([N+]([O-])=O)=C(C=C(NC2C=CC(I)=CC=2F)C=1)OC1C=C(NS(CC)(=O)=O)C=CC=1>N1C=CC=CC=1>[F:21][C:19]1[CH:18]=[C:8]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:7]([N+:22]([O-:24])=[O:23])=[C:6]([CH:20]=1)[O:5][C:4]1[CH:3]=[C:2]([NH:1][S:57]([CH2:55][CH3:56])(=[O:59])=[O:58])[CH:27]=[CH:26][CH:25]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2[N+](=O)[O-])c1
Agent: CCS(=O)(=O)Nc1cccc(Oc2cc(Nc3ccc(I)cc3F)cc(F)c2[N+](=O)[O-])c1
Agent: Nc1cccc(Oc2cc(F)c([N+](=O)[O-])c(Nc3ccc(I)cc3F)c2)c1
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
11.7 g 3-(3-aminophenoxy)-5-fluoro-N-(2-fluoro-4-iodophenyl)-2-nitroaniline (24.3 mmol, 1. eq.; containing a minor amount of the regioisomeric 5-(3-aminophenoxy)-3-fluoro-N-(2-fluoro-4-iodophenyl)-2-nitroaniline) was dissolved in 98 mL pyridine, set under an atmosphere of nitrogen and treated sequentially with 3.4 mL ethyl sulfonyl chloride (36.4 mmol, 1.5 eq.; dissolved in pyridine). The resulting reaction mixture was stirred at rt for 20 h after which LCMC analysis showed final turnover. The reaction mixture was quenched by addition of water and diluted with ethyl acetate and phases were separated. The separated aqueous layer was reextracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 14.8 g of the crude target compound (which contained a minor amount of the regioisomeric N-(3-{3-fluoro-5-[(2-fluoro-4-iodophenyl)amino]-2-nitrophenoxy}-phenyl)ethanesulfonamide) which was used without further purification in the subsequent transformations.
Reaction SMILES: [CH:1]1([C:4]2[CH:32]=[CH:31][C:7]([CH2:8][O:9][C:10]3[CH:15]=[CH:14][C:13]([CH:16]4[CH2:19][N:18]([C:20]([C:22]5[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][N:23]=5)=[O:21])[CH2:17]4)=[CH:12][C:11]=3[O:29][CH3:30])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].C1(C)C=CC(S(O[CH2:49][C@H:50]2[CH2:54][O:53][C:52]([CH3:56])([CH3:55])[O:51]2)(=O)=O)=CC=1.O>CN(C=O)C>[CH:1]1([C:4]2[CH:32]=[CH:31][C:7]([CH2:8][O:9][C:10]3[CH:15]=[CH:14][C:13]([CH:16]4[CH2:19][N:18]([C:20]([C:22]5[CH:27]=[C:26]([O:28][CH2:49][C@H:50]6[CH2:54][O:53][C:52]([CH3:56])([CH3:55])[O:51]6)[CH:25]=[CH:24][N:23]=5)=[O:21])[CH2:17]4)=[CH:12][C:11]=3[O:29][CH3:30])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: COc1cc(C2CN(C(=O)c3cc(O)ccn3)C2)ccc1OCc1ccc(C2CC2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COC(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C2CN(C(=O)c3cc(OC[C@H]4COC(C)(C)O4)ccn3)C2)ccc1OCc1ccc(C2CC2)cc1
Temperature: 100 °C
Reaction time: 13 h
Yield: 47.4 %

Procedure:
To a suspension of {3-[4-(4-cyclopropylbenzyloxy)-3-methoxyphenyl]-azetidin-1-yl}-(4-hydroxypyridin-2-yl)-methanone (0.45 g) prepared in a manner similar to Example (6) using 4-hydroxypyridine-2-calboxylic acid and K2CO3 (0.21 g) in DMF (8.0 mL) was added (R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl toluene-4-sulfonate (0.33 g). The reaction mixture was stirred at 100° C. for 13 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over MgSO4. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (Developing solvent: hexane/ethyl acetate=1/2) to give the title compound (0.27 g, 49%).
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([CH3:22])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:21])[CH2:6][CH2:5]1.[CH3:23]OC(OC)(C)C.[NH+]1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.N1C=CC=CC=1>C(OCC)(=O)C>[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([CH3:22])[C:9](=[CH:10][CH2:11]2)[CH:8]=[C:7]([O:21][CH3:23])[CH2:6][CH2:5]1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](F)C[C@]2(C)C(=O)CC[C@@H]12
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC1=CC2=CC[C@@H]3[C@H]([C@@H](F)C[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1
Reaction time: 8 h

Procedure:
10.0 g of 11β-fluoroandrost-4-ene-3,17-dione [U.S. Pat. No. 3,966,713 (1976)] is stirred under reflux with 60 ml of dimethoxypropane and 1.0 g of pyridinium-4-toluenesulfonate. After 8 hours, 1 ml of pyridine is added, the mixture is diluted with ethyl acetate, washed neutral with water, and dried. The crude product is chromatographed on silica gel with an acetone-hexane gradient. Yield: 7.8 g of 11β-fluoro-3-methoxyandrosta-3,5-dien-17-one as a foam.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][C:9]#[N:10].[CH2:11]([N:18]1[CH2:23][CH:22]2[CH2:24][CH:19]1[CH2:20][NH:21]2)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[CH2:11]([N:18]1[CH2:23][CH:22]2[CH2:24][CH:19]1[CH2:20][N:21]2[CH2:8][C:9]#[N:10])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1ccc(CN2CC3CC2CN3)cc1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: N#CCN1CC2CC1CN2Cc1ccccc1

Procedure:
Finely ground potassium carbonate, as well as 1.3 mL of freshly distilled chloroacetonitrile were added to a solution of 3 g of 2-benzyl-2,5-diazabicyclo[2.2.1]heptane in 40 mL of anhydrous toluene and refluxed for 10 hours with vigorous stirring. The solution was cooled, filtered and evaporated. Bulb tube distillation (boiling point: 110°–120° C. at 0.01 mbar) resulted in 3.57 g of 140 as a colorless oil (97% of the theoretical yield).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:3]=1.[F:40][C:41]1[CH:42]=[C:43]([CH:60]=[CH:61][CH:62]=1)[CH2:44][N:45]1[CH:49]=[C:48](C2OC(C)(C)C(C)(C)O2)[C:47]([CH3:59])=[N:46]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.C(O)C.O>[F:40][C:41]1[CH:42]=[C:43]([CH:60]=[CH:61][CH:62]=1)[CH2:44][N:45]1[CH:49]=[C:48]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)[CH:14]=[CH:15][CH:16]=4)[CH:9]=3)[N:4]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:3]=2)[C:47]([CH3:59])=[N:46]1
Reactant: Cc1nn(Cc2cccc(F)c2)cc1C1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cccc(N5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cn(Cc4cccc(F)c4)nc3C)c3cc(-c4cccc(N5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc32)cc1
Yield: 59.6 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 4-(3-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (intermediate 39) (200 mg, 0.308 mmol) was coupled with 1-(3-fluorobenzyl)-3-methyl-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-1H-pyrazole (intermediate 12) (244 mg, 0.772 mmol) in sodium carbonate (98 mg, 0.926 mmol), Pd(PPh3)2Cl2 (11 mg, 0.015 mmol), toluene/ethanol/water (3/3/3 ml). This afforded 130 g (59.6% yield) after purification by column (Silica gel 60/120) using 1.5% of methanol in chloroform as eluent. MS: m/z=710.3 (M+1).
Reaction SMILES: [ClH:1].[O:2]=[C:3]1[N:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C@@H:8]2[CH:7]=[CH:6][CH2:5][C@@H:4]1[NH:14]C(=O)OC(C)(C)C>O1CCOCC1>[ClH:1].[NH2:14][C@@H:4]1[C:3](=[O:2])[N:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C@@H:8]2[CH:7]=[CH:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC=C[C@H]2CCCCN2C1=O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CC=C[C@H]2CCCCN2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of HCl (4.0 N in 1,4-dioxane, 2.33 mL, 9.32 mmol) was added to a 0° C. solution of tert-butyl (7S,10aR,Z)-6-oxo-1,2,3,4,6,7,8,10a-octahydropyrido[1,2-a]azepin-7-ylcarbamate (653 mg, 2.33 mmol) in 1,4-dioxane (0.93 mL). The reaction mixture was then stirred at rt for 1 hr. The reaction mixture was concentrated and dried under vacuum to give (7S,10aR,Z)-7-amino-1,2,3,4,7,8-hexahydropyrido[1,2-a]azepin-6(10aH)-one hydrochloride (504 mg, 2.33 mmol, 100% yield) as a tan solid. Anal. Calcd. for C10H16N2O m/z 180.2. found: 181.0 (M+H)+.