Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N+]([C:18]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21])([O-])=O.Cl>CN(C)C=O>[CH2:1]([S:8][C:18]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Reactant: SCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1cccc([N+](=O)[O-])c1SCc1ccccc1
Temperature: 0 °C

Procedure:
6.85 g (0.055 mol) of benzyl mercaptan are dissolved in 150 ml of dimethylformamide. The batch is then cooled to 0° C. and 15.2 g (0.11 mol) of potassium carbonate are added. 10.6 g (0.050 mol) of 2,3-dinitrobenzoic acid are then added in portions at from 0° to 5° C. and the internal temperature is afterwards raised to room temperature over a period of 24 hours. The reaction mixture is then poured onto ice/water and acidified with hydrochloric acid. The resulting product is filtered, washed with water and dried. Yield: 11.8 g (82% of the theoretical yield); m.p. 152°-153° C.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[C:15]([CH:20]=[O:21])=[N:16][O:17][C:18]=2[CH3:19])=[O:7])=[CH:4][CH:3]=1.[CH2:24]1COCC1.C[Mg]Cl.[Cl-].[NH4+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[C:15]([CH:20]([OH:21])[CH3:24])=[N:16][O:17][C:18]=2[CH3:19])=[O:7])=[CH:22][CH:23]=1
Reactant: Cc1onc(C=O)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Reactant: C1CCOC1
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: Cc1onc(C(C)O)c1-c1ccccc1C(=O)c1ccc(Cl)cc1

Procedure:
To a resealable vial was added 4-(2-(4-chlorobenzoyl)phenyl)-5-methylisoxazole-3-carbaldehyde from Example 15 (0.100 g, 0.307 mmol) and THF (2.0 mL). The vial was sealed and cooled to −78° C. before addition of methylmagnesium chloride (0.107 mL, 0.322 mmol). The reaction was stirred at −78° C. for 30 min before addition of ammonium chloride solution and water. The aqueous was extracted with EtOAc and the combined layers washed with brine, dried over Na2SO4, filtered, and concentrated to afford crude (4-chlorophenyl)(2-(3-(1-hydroxyethyl)-5-methylisoxazol-4-yl)phenyl)methanone (0.092 g, 0.269 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][C:6](=[O:7])[C:5]2=[CH:11][C:12]=1[S:13](=[O:16])(=[O:15])[NH2:14].N[CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH2:20][CH2:19]1.C(O)CCCC.O=C1C2C(=CC=CC=2)C(=O)N1>CCCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6](=[O:7])[N:8]([CH:18]3[CH2:19][CH2:20][N:21]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[CH3:31])[CH2:22][CH2:23]3)[C:9]2=[O:10])=[CH:11][C:12]=1[S:13]([NH2:14])(=[O:16])=[O:15]
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)NC2=O
Reactant: Cc1ccccc1CN1CCC(N)CC1
Agent: O=C1NC(=O)c2ccccc21
Solvent: CCCCCO
Solvent: CCCCCCC
Product: Cc1ccccc1CN1CCC(N2C(=O)c3cc(Cl)c(S(N)(=O)=O)cc3C2=O)CC1

Procedure:
A mixture of 4-chloro-5-sulfamoylphthalimide (5.74 g., 0.022 mole) and 4-amino-1-[(2-methylphenyl)methyl]piperidine (4.5 g., 0.022 mole) in 85 ml. of n-pentanol was reacted according to the procedure of Example 1(a). Addition of n-heptane to the reaction mixture afforded 7.9 g. (80%) of the 1,3-dioxoisoindole product, m.p. 283°-243°. Crystallization of this material from DMF-methanol provided analytically pure 6-chloro-2,3-dihydro-2-[1-[(2-methylphenyl)methyl]-4-piperidinyl]-1,3-dioxo-1H-isoindole-5-sulfonamide, m.p. 244°-245° (dec.).
Reaction SMILES: S([CH2:5][CH2:6][C:7]#[C:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=1)(C)(=O)=O.[CH2:16]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:16]([CH:23]1[CH2:28][CH2:27][N:26]([CH2:5][CH2:6][C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: Cc1cccc(C#CCCS(C)(=O)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cccc(C#CCCN2CCC(Cc3ccccc3)CC2)c1
Yield: 31.5 %

Procedure:
A mixture of 1-mesyl-4-(3-methylphenyl)but-3-yne (214 mg, 0.900 mmol), 4-benzylpiperidine (189 mg, 1.08 mmol) and K2CO3 (370 mg, 2.67 mmol) in 10 mL of CH3CN is refluxed for 12 hr. The mixture is filtered and washed with EtOAc (3×15 mL). The filtrate is evaporated in vacuo and is purified by flash chromatography to give the product as an oil (90 mg, 31%): 1H NMR (CDCl3) 1.40 (m, 2 H), 1.51 (m, 1 H), 1.65 (m, 2 H), 2.05 (t, J=6.6 Hz, 2 H), 2.31 (s, 3 H), 2.54 (m, 2 H), 2.68 (m, 4 H), 2.97 (d, J=11.4 Hz, 2 H), 7.13-7.28 (m, 9 H).
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[N+:16]([O-:18])=O.[N-:19]=[N+]=[N-].[Na+]>C(O)CO>[N:19]1[O:18][N:16]=[C:3]2[CH:4]=[C:5]([C:6]([N:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)=[O:7])[CH:14]=[CH:15][C:2]=12
Reactant: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)N1CCCCC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: OCCO
Product: O=C(c1ccc2nonc2c1)N1CCCCC1
Temperature: 50 °C
Yield: 74.7 %

Procedure:
4-Chloro-3-nitro-benzoylpiperidine (539.2 g, 2.00 mol) was dissolved in 2.93 L ethylene glycol in a 5-L flask with stirring and heating to 50° C. To this solution, sodium azide (137.0 g, 2.10 moles) was added in portions over 40 min. When the addition was complete, the temperature was increased to 120° C. during 2.5 hr and maintained at this temperature for 3 hr. The solution was allowed to cool to 50° C., at which time additional sodium azide (65.3 g, 1.00 moles) was added over 5 min. The temperature was increased to 120° C. during 2.5 hr and maintained at this temperature for 4.5 hr until gas evolution had ceased. The solution was allowed to cool to room temperature, at which time the mixture was partitioned between water and ethyl acetate (1.5 L each). The aqueous phase was extracted three times with ethyl acetate (300 mL). The combined organic phases were washed with 30 mL water, twice with saturated NaCl (200 mL), and finally dried over anhydrous Na2SO4. The filtered solution was evaporated to yield 345.5 g of crude 1-(benzofurazan-5-ylcarbonyl)piperidine.
Reaction SMILES: Cl.[CH:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14](=[O:24])[C:15]([NH:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[O:16])=[CH:6]1)([CH3:4])[CH3:3].C([O-])([O-])=O.[K+].[K+].[CH2:31](Br)[CH2:32][CH2:33][CH3:34]>C(#N)C>[CH2:31]([N:21]1[CH2:20][CH2:19][CH:18]([NH:17][C:15](=[O:16])[C:14]([C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=2)=[O:24])[CH2:23][CH2:22]1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCCBr
Reactant: CC(C)n1cc(C(=O)C(=O)NC2CCNCC2)c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCN1CCC(NC(=O)C(=O)c2cn(C(C)C)c3ccccc23)CC1
Temperature: 65 °C
Reaction time: 72 h
Yield: 28.8 %

Procedure:
The title compound was prepared according to general procedure E described in Scheme 2. 2-(1-Isopropyl-1H-indol-3-yl)-2-oxo-N-(piperidin-4-yl)acetamide hydrochloride (200 mg, 0.64 mmol) was treated with acetonitrile (3 mL), K2CO3 (265 mg, 1.91 mmol), and n-butyl bromide (175 mg, 1.28 mmol). The reaction mixture was stirred at 65° C. for 72 h and was then concentrated under reduced pressure. The crude material was purified on silica gel (Biotage, 2-10% MeOH/DCM, 30 min.) to provide the title compound as a pink solid (68 mg, 29% yield): 1H NMR (400 MHz, CDCl3): δ 9.11 (s, 1H), 8.43 (t, 1H), 7.56 (d, 1H), 7.43 (q, 1H), 7.35 (t, 2H), 4.71 (m, 1H), 3.90 (m, 1H), 3.03 (d, 2H), 2.48 (d, 2H), 2.31 (t, 2H), 2.05 (d, 2H), 1.80 (m, 2H), 1.61 (d+m, 8H), 1.34 (m, 2H), 0.94 (t, 3H);
Reaction SMILES: BrC1C=NC(N2C3C(=CC=C(C(N(C)C)=O)C=3)C(SC)=C2)=NC=1.Br[C:25]1[CH:30]=[C:29]([NH2:31])[CH:28]=[CH:27][N:26]=1.CC1C=CN=C(C2C=NC(N3C4C(=CC=C(C(OC)=O)C=4)C(SC)=C3)=NC=2)C=1.CC1C=CN=C([C:67]2[CH:68]=[N:69][C:70]([N:73]3[C:81]4[C:76](=[CH:77][CH:78]=[C:79]([C:82]([N:84]5[CH2:88]CC[CH2:85]5)=[O:83])[CH:80]=4)[C:75]([S:89]([CH3:91])=[O:90])=[CH:74]3)=[N:71][CH:72]=2)C=1>>[NH2:31][C:29]1[CH:28]=[CH:27][N:26]=[C:25]([C:67]2[CH:72]=[N:71][C:70]([N:73]3[C:81]4[C:76](=[CH:77][CH:78]=[C:79]([C:82]([N:84]([CH3:85])[CH3:88])=[O:83])[CH:80]=4)[C:75]([S:89]([CH3:91])=[O:90])=[CH:74]3)=[N:69][CH:68]=2)[CH:30]=1
Reactant: Cc1ccnc(-c2cnc(-n3cc(S(C)=O)c4ccc(C(=O)N5CCCC5)cc43)nc2)c1
Reactant: Nc1ccnc(Br)c1
Agent: COC(=O)c1ccc2c(SC)cn(-c3ncc(-c4cc(C)ccn4)cn3)c2c1
Agent: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)N(C)C)ccc12
Product: CN(C)C(=O)c1ccc2c(S(C)=O)cn(-c3ncc(-c4cc(N)ccn4)cn3)c2c1

Procedure:
1-(5-Bromopyrimidin-2-yl)-N,N-dimethyl-3-(methylthio)-1H-indole-6-carboxamide was converted into a boronic ester that was reacted in a Suzuki reaction with 2-bromopyridin-4-amine and the resulting product was then oxidized towards the sulfoxide (analogously to the protocols 269a) and 269d), respectively). White solid. Yield: 0.095 g
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:37])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([CH2:35][CH3:36])[CH:30]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:35]([C:31]1[CH:30]=[C:29]([C:25]2[CH:24]=[C:23]([C:21]3[CH2:20][C:19](=[O:37])[NH:18][C:9]4[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:28]=[CH:27][CH:26]=2)[CH:34]=[CH:33][N:32]=1)[CH3:36]
Reactant: CCc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (2-{3-[3-(2-ethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M138) (0.27 g, 0.51 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (158 mg, 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[C:13]1(C)C=CC(S(O)(=O)=O)=C[CH:14]=1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)Cc1ccc(OC)cc1

Procedure:
A solution of 4-methoxyphenylacetic acid (2 g) and para-toluensulfonic acid (230 mg) in 30 ml of ethanol is refluxed for 2 hours. The solvent is evaporated under reduced pressure and the residue is suspended in a saturated aqueous solution of sodium hydrogencarbonate and extracted twice with ethyl acetate. The organic extracts are collected, washed with water and dried over sodium sulfate to give, after evaporation of the solvent under reduced pressure, 2.14 g of the product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[C:21]([C:24]1[N:29]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][C:39]([CH2:42][C:43](O)=[O:44])=[CH:38][C:37]=3[Cl:46])=[CH:32][CH:31]=2)[C:27]([CH3:47])=[N:26][C:25]=1[CH3:48])(=[O:23])[NH2:22].Cl.CN(C)CCCN=C=NCC.N1(O)C2C=CC=CC=2N=N1>CN(C=O)C>[C:21]([C:24]1[N:29]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][C:39]([CH2:42][C:43]([N:1]4[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]4)=[O:44])=[CH:38][C:37]=3[Cl:46])=[CH:32][CH:31]=2)[C:27]([CH3:47])=[N:26][C:25]=1[CH3:48])(=[O:23])[NH2:22]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Cc1nc(C)c(-c2ccc(-c3ccc(CC(=O)O)cc3Cl)cc2)nc1C(N)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(C(=O)Cc2ccc(-c3ccc(-c4nc(C(N)=O)c(C)nc4C)cc3)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 104.6 %

Procedure:
A mixture of ethyl piperidine-4-carboxylate (90 mg, 0.57 mmol) and N-ethyl-N-isopropylpropan-2-amine (99 μL, 0.57 mmol) in DMF (342 μL) were treated with a solution of 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetic acid (Example 1; 205 mg, 0.52 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (124 mg, 0.65 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (70.0 mg, 0.52 mmol) and N-ethyl-N-isopropylpropan-2-amine (99 μL, 0.57 mmol) in DMF (2049 μL) at RT. The resulting solution was stirred at RT for 20 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (5 mL), and washed with water (5 mL). The organic layer was evaporated to afford ethyl 1-(2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetyl)piperidine-4-carboxylate (291 mg, 105%) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:33]([C:36]1[CH:41]=[CH:40][C:39]([C:42](=[O:44])[CH3:43])=[CH:38][CH:37]=1)=[C:34]=[O:35]>ClCCl>[C:42]([C:39]1[CH:40]=[CH:41][C:36]([NH:33][C:34]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:35])=[CH:37][CH:38]=1)(=[O:44])[CH3:43]
Reactant: CC(=O)c1ccc(N=C=O)cc1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.9 %

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (80 mg, 0.21 mmol) (from Example 25a supra) in dichloromethane (2 mL) was added triethylamine (53.8 mg, 0.525 mmol) (Aldrich), followed by the addition of 1-(4-isocyanato-phenyl)-ethanone (41.2 mg, 0.25 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-acetyl-phenyl)-amide as a white solid (Yield 45 mg, 39%).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[F:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>O1CCCC1>[CH:5]([NH:14][C:13]1[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=1[F:11])=[O:7]
Reactant: Nc1ccccc1F
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: C1CCOC1
Product: O=CNc1ccccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an acetic anhydride (15.5 mL) was added dropwise formic acid (6.1 mL) at 0 degrees under an atmosphere of argon. The mixture was stirred at 50 degrees for 2 hours. After the reaction mixture was cooled to room temperature, it was diluted with tetrahydrofuran (THF; 10 mL). To the diluted solution was added 2-fluoroaniline (5.56 g) in THF (20 mL) at room temperature and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give the title compound having the following physical data. The obtained title compound was used to next reaction without further purification.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[Br:12][C:13]1[CH:14]=[C:15](/[CH:19]=[CH:20]/[C:21](O)=[O:22])[CH:16]=[CH:17][CH:18]=1>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:21](=[O:22])/[CH:20]=[CH:19]/[C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([Br:12])[CH:14]=1)[CH2:4]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)/C=C/c1cccc(Br)c1
Agent: Cl
Product: O=C(/C=C/c1cccc(Br)c1)N[C@H]1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(3-bromophenyl)propenoic acid; the compound was purified by chromatography on silica gel using ammoniated methanol/chloroform mixtures as the eluent; MS (ES+) 335, 337 (MH+).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4[CH:28]=O)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:31][N:32]1[CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:26][CH2:27]3)[CH:17]=[C:16]4[CH2:28][N:35]3[CH2:36][CH2:37][CH2:38][N:32]([CH3:31])[CH2:33][CH2:34]3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Reactant: CN1CCCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCCN(C)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
The product of step iii) (0.1 g) was dissolved in dichloromethane (10 mL) and 1-methyl-1,4-diazepane (0.062 mL) added. The mixture was stirred at room temperature for 5 minutes then sodium triacetoxyborohydride (0.16 g) was added. The mixture was allowed to stand and the solvent allowed to evaporate. Methanol (5 mL) was added and the solution purified directly by HPLC to give the title compound as a solid (30 mg).
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[C:21](O)=[O:22].C(N(CC)C(C)C)(C)C.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.[NH2:53][CH2:54][CH2:55][NH:56][C:57](=[O:63])[O:58][C:59]([CH3:62])([CH3:61])[CH3:60]>CN(C)C=O>[O:20]=[C:12]1[CH2:13][CH2:14][C@@:15]2([CH3:16])[C:10]([CH2:9][CH2:8][C@@H:7]3[C@@H:17]2[CH2:18][CH2:19][C@@:2]2([CH3:1])[C@H:6]3[CH2:5][CH2:4][CH:3]2[C:21]([NH:53][CH2:54][CH2:55][NH:56][C:57](=[O:63])[O:58][C:59]([CH3:60])([CH3:62])[CH3:61])=[O:22])=[CH:11]1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCNC(=O)C1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To 0.49 g of 4-androsten-3-one-17β-carboxylic acid was added N,N-dimethylformamide (3 ml), N,N-diisopropylethylamine (0.55 ml) and O—(N-Succinimidyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.48 g). On stirring at room temperature (under an atmosphere of nitrogen) for 1.5 hours tert Butyl N-(2-aminoethyl)carbamate (0.25 g) was added. The mixture was stirred at room temperature for 3 days after which time the volatile components were removed on a rotary evaporator. Flash column chromatography was performed and the relevant fractions combined and stripped of solvent using a rotary evaporator. This gave 0.50 g of the desired material (Formula XIII).
Reaction SMILES: [OH:1][C@H:2]([CH3:12])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH3:13]N(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.F[B-](F)(F)F.C[O+](C)C.O>C(Cl)Cl>[CH3:13][O:1][C@H:2]([CH3:12])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9]
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Reactant: C[C@@H](O)CNC(=O)OC(C)(C)C
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: O
Product: CO[C@H](C)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
To a solution of tert-butyl [(2R)-2-hydroxypropyl]carbamate (2.7 g) in CH2Cl2 (41 ml) were added N,N,N′,N′-tetramethylnaphthalene-1,8-diamine (3.63 g) and trimethyloxonium tetrafluoroborate (2.51 g), and the whole was stirred for 3 hours at room temperature. Water was added to the mixture, and the whole was extracted with EtOAc, and the extract was washed with water and brine and dried over MgSO4. Concentration under reduced pressure gave tert-butyl [(2R)-2-methoxypropyl]carbamate (2.73 g).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH2:11][N:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:23]=[C:22]([C:24]4[C:28]([C:29]([F:32])([F:31])[F:30])=[C:27]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=5)[O:26][N:25]=4)[O:21][N:20]=3)=[CH:15][CH:14]=2)[CH2:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:27]1[O:26][N:25]=[C:24]([C:22]2[O:21][N:20]=[C:19]([C:16]3[CH:17]=[CH:18][C:13]([CH2:12][N:10]4[CH2:11][CH:8]([C:6]([OH:7])=[O:5])[CH2:9]4)=[CH:14][CH:15]=3)[N:23]=2)[C:28]=1[C:29]([F:31])([F:30])[F:32]
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(-c4noc(-c5ccccn5)c4C(F)(F)F)n3)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C1CN(Cc2ccc(-c3noc(-c4noc(-c5ccccn5)c4C(F)(F)F)n3)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl-1-(4-(5-(5-(pyridin-2-yl)-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (previous reaction) in dichloromethane (0.5 mL) was added trifluoroacetic acid (0.5 mL), and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was treated with triethylamine and re-concentrated. The product mixture was purified by flash silica gel chromatography using a mixture of methanol, dichloromethane, and ammonium hydroxide (10:90:0-10:90:1-15:85:1-20:80:1) to give 1-(4-(5-(5-(pyridin-2-yl)-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acid (0.007 g, 0.015 mmol) as an off-white solid. The product had an HPLC retention time=2.33 min.—Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=472.0. 1H NMR (500 MHz, methanol-d3) δ ppm 3.50 (quin, J=8.25 Hz, 1H), 4.21-4.29 (m, 4H), 4.46 (s, 2H), 7.66-7.71 (m, 3H), 8.02-8.05 (m, 1H), 8.08-8.13 (m, 1H), 8.28 (d, J=8.25 Hz, 2H), and 8.83-8.85 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([C:6](=[O:13])[C:7](=[O:12])[NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]([CH3:33])[CH3:32])(=[O:30])=[O:29])=[CH:24][CH:23]=1>CN(C=O)C>[Br:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([C:6](=[O:13])[C:7](=[O:12])[N:8]2[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([N:31]([CH3:32])[CH3:33])(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1
Reactant: CN(C)S(=O)(=O)c1ccc(CBr)cc1
Reactant: Cc1c(Br)ccc2c1NC(=O)C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(Br)ccc2c1N(Cc1ccc(S(=O)(=O)N(C)C)cc1)C(=O)C2=O
Reaction time: 0.5 h
Yield: 10.8 %

Procedure:
To a solution of 6-bromo-7-methyl-1H-indole-2,3-dione (2.0 g, 8.33 mmol) in DMF (25 ml) was added potassium carbonate (2.3 g, 16.6 mmol). After stirring at this temperature for 30 minutes, was added 4-bromomethyl-N,N-dimethyl-benzenesulfonamide (3.0 g, 10.83 mmol). The reaction mixture was stirred at room temperature for six hours. It was then partitioned between water and ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated under vacuum to give the crude product which was chromatographed on flash silica gel eluting with 20% ethyl acetate in hexane, providing the title compound of 12A (0.392 g, 11% yield).