Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:10]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:9]1=[O:30])(=O)=O.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>ClCCl>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([N:10]2[C@@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[CH:14]=3)[CH2:12][N:8]([CH2:7][CH2:6][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[C:9]2=[O:30])=[CH:24][CH:25]=1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)OCCN1C[C@H](c2cccc(C(F)(F)F)c2)N(c2ccc(Cl)cc2)C1=O
Solvent: ClCCl
Product: O=C1N(CCN2CCOCC2)C[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Cl)cc1
Reaction time: 3 h

Procedure:
To a solution of (S)-2-(3-(4-chlorophenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)ethyl methanesulfonate (30 mg, 0.065 mmol) in anhydrous dichloromethane (3 mL) is added morpholine (16.9 mg, 0.194 mmol). After 3 h at room temperature, the residue is purified by preparatory LC/MS to provide the title compound; 1H NMR (CD3OD, 400 MHz) δ 7.71 (s, 1H), 7.62-7.53 (m, 3H), 7.43 (d, J=9.2 Hz, 2H), 7.25 (d, J=9.2 Hz, 2H), 5.58 (dd, J=9.2, 6.2 Hz, 1H), 4.04 (t, J=9.2 Hz, 1H), 3.95-4.59 (m, 6H), 3.49-3.26 (m, 4H), 3.24 (dd, J=9.0, 6.2 Hz, 1H), 3.19-3.01 (m, 2H); HPLC-MS calculated for C22H24ClF3N3O2 (M+H+) 454.1, found 454.0.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]([C:7]1[N:11]=[C:10]([C@H:12]([N:24]([C:26](=[O:47])[C@H:27]([NH:39]C(OC(C)(C)C)=O)[CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)[CH3:25])[CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[O:9][N:8]=1)=[O:6])[CH3:3].FC(F)(F)C(O)=O>ClCCl>[CH3:3][CH:2]([O:4][C:5]([C:7]1[N:11]=[C:10]([C@H:12]([N:24]([C:26](=[O:47])[C@H:27]([NH2:39])[CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)[CH3:25])[CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[O:9][N:8]=1)=[O:6])[CH3:1]
Reactant: CC(C)OC(=O)c1noc([C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)[C@@H](Cc2ccc3ccccc3c2)NC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)OC(=O)c1noc([C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)[C@H](N)Cc2ccc3ccccc3c2)n1
Reaction time: 0.17 h
Yield: 124.2 %

Procedure:
5-{(1R)-1-[N-((2R)-2-tert-Butoxycarbonylamino-3-(2-naphthyl)propionyl)-N-methylamino]-2-(2-naphthyl)ethyl}-[1,2,4]oxadiazole-3-carboxylic acid (2-propyl)ester (2.1 g, 3.3 mmol) was suspended in a saturated mixture of trifluoroacetic acid and dichloromethane (1:1, 60 ml). After 10 min at 20° C., the reaction mixture was concentrated in vacuo to give 2.2 g of 5-{(1R)-1-[N-((2R)-2-amino-3-(2-naphthyl)propionyl)-N-methylamino]-2-(2-naphthyl)ethyl}-[1,2,4]oxadiazole-3-carboxylic acid (2-propyl)ester, trifluoroacetate, that was used for the next step without further purification.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:18]([C@@H:20]1[C@@H:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:23][N:22]([C@H:31]([CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)[C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)=[O:33])[CH2:21]1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]1([C:7]2[S:8][C:9]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][C@@H:20]4[C@@H:24]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH2:23][N:22]([C@H:31]([CH:44]5[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]5)[C:32]([O:34][CH2:35][C:36]5[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=5)=[O:33])[CH2:21]4)[CH2:14][CH2:13]3)=[CH:10][N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Reactant: c1ccc(-c2ncc(C3CCNCC3)s2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(c4cnc(-c5ccccc5)s4)CC3)[C@@H](c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To 12 mg of 4-(2-phenyl-thiazol-5-yl)-piperidine (from Step B) in 3 ml of DCE was added 35 mg of a-(R)-(3-(R)-formyl4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid, p-methoxybenzyl ester (prepared above as Aldehyde 5) followed by 19 mg of sodium triacetoxyborohydride. The reaction was stirred overnight at room temperature. The solvent was evaporated under reduced pressure. The residue was purified by flash chromatography with 10% EtOAc in hexane followed by 50% EtOAc in hexane to give 28 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[NH:5][C:6](=[O:9])[CH2:7][CH3:8].C([O-])(=O)C.[Na+].[CH:18]1([C:21](Cl)=[O:22])[CH2:20][CH2:19]1.[Cl-]>C(O)(=O)C>[C:6]([NH:5][C:4]1[CH:3]=[C:2]([CH:12]=[CH:11][CH:10]=1)[NH:1][C:21]([CH:18]1[CH2:20][CH2:19]1)=[O:22])(=[O:9])[CH2:7][CH3:8]
Reactant: O=C(Cl)C1CC1
Reactant: CCC(=O)Nc1cccc(N)c1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCC(=O)Nc1cccc(NC(=O)C2CC2)c1

Procedure:
Meta-aminopropionanilide, 13.1 g. (0.08 mole) is dissolved in 200 ml. of a 50/50 v/v mixture of glacial acetic acid and saturated sodium acetate solution. To this solution is added 9.2 g. (0.088 moles) of cyclopropane carbonyl chloride. The chloride is added slowly with adequate stirring and cooling. The product, which crystallizes from the solution, is collected by filtration. The product is consecutively washed with a 5 percent solution of sodium hydroxide, a 5 percent solution of hydrochloric acid and water. After washing, the crystals are dried. There is obtained 15 g. (81 percent of theory) of the title compound, m.p. 185°-186° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.FC(F)(F)C(O)=O.[CH3:25][S:26]([N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1)(=[O:28])=[O:27]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[O:9])=[CH:6][CH:5]=[C:4]([NH:35][CH:32]2[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH2:31]2)[N:3]=1
Reactant: Nc1nc(Cl)ccc1C(=O)c1ccccc1F
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCC(Nc2ccc(C(=O)c3ccccc3F)c(N)n2)CC1

Procedure:
The title compound was prepared from (2-Amino-6-chloro-pyridin-3-yl)-(2-fluoro-phenyl)-methanone (Example 7) and 1-methanesulfonyl-piperidin-4-ylamine (Step A, Example 6) using the procedure described in Step B. Example 6. HRMS, observed: 392.1329, calcd for M+: 392.1318.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([S:14]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C@@H:18]3[CH3:30])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.[F:31][C:32]1[CH:33]=[C:34]([CH2:38][CH2:39][NH2:40])[CH:35]=[CH:36][CH:37]=1>>[F:31][C:32]1[CH:33]=[C:34]([CH:35]=[CH:36][CH:37]=1)[CH2:38][CH2:39][NH:40][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([S:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][C@@H:18]3[CH3:30])(=[O:15])=[O:16])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1cccc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1cccc(F)c1
Product: C[C@H]1CNCCN1S(=O)(=O)c1cccc(-c2ccnc(NCCc3cccc(F)c3)n2)c1

Procedure:
Intermediate 153 from above was coupled with 2-(3-fluorophenyl)ethanamine following procedure F. The product was deprotected by procedure G2. LC-MS showed the product had the expected M+H+ of 456. 1H NMR (Varian 300 MHz, MeOD-d6, shifts relative to the solvent peak at 3.31 ppm) δ 8.6 (d, 1H) 8.5 (d, 1H) 8.4 (d, 1H), 8.1 (d, 1H), 7.8 (t, 1H), 7.6 (d, 1H), 7.2 (t, 1H), 7.1 (d, 1H), 7.0 (d, 1H), 6.8 (d, 1H), 3.9 (m, 3H), 3.4 (m, 1H), 3.3 (m, 2H), 3.2 (m, 2H), 3.1 (m, 1H), 3.0 (t, 2H), 1.2 (d, 3H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[CH:14][C:13]=1[F:23])=[O:11].Br[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=1>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[C:17]([N:18]3[N:19]=[CH:20][CH:21]=[N:22]3)=[CH:16][CH:15]=[CH:14][C:13]=2[F:23])=[O:11])=[N:26][CH:27]=1
Reactant: Clc1ccc(Br)nc1
Reactant: C[C@@H]1CCCN(C(=O)c2c(F)cccc2-n2nccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2c(F)cccc2-n2nccn2)[C@@H]1CNc1ccc(Cl)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. ESI-MS (m/z): 429 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([CH2:19][CH2:20][N:15]3[C:14](=[O:21])[CH:13]=[C:12]2[CH3:22])[CH:18]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[CH3:25]N(C)C=O.CC(C)([O-])C.[K+].S(OC)(OC)(=O)=O>O>[F:5][C:4]([F:7])([F:6])[C:3]([C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([CH2:19][CH2:20][N:15]3[C:14](=[O:21])[CH:13]=[C:12]2[CH3:22])[CH:18]=1)([O:8][CH3:25])[C:2]([F:1])([F:23])[F:24]
Reactant: Cc1cc(=O)n2c3c(cc(C(O)(C(F)(F)F)C(F)(F)F)cc13)CC2
Reactant: CN(C)C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COC(c1cc2c3c(c1)c(C)cc(=O)n3CC2)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Yield: 49 %

Procedure:
To a stirred mixture of 3.5 g of 1,2-dihydro-8-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-6-methyl-4H-pyrrolo[3,2,1-ij]quinolin-4-one and 20 ml of dry dimethylformamide is added 1.3 g (0.012 mole) of potassium tert-butoxide in a dry nitrogen atmosphere. The mixture is heated gently to 100° and is allowed to cool. Then 1 ml (1.35 g, 0.011 mole) of dimethyl sulfate is added, and the mixture is warmed gently to 100°. The mixture is allowed to cool to room temperature and is poured into 100-200 ml of water. The precipitate is filtered off and then is triturated with 10% sodium hydroxide solution. The insoluble material is filtered off, washed with water, and dried. Recrystallization from alcohol gives 1.8 g (49%) of 1,2-dihydro-8-[2,2,2-trifluoro-1-methoxy-1-(trifluoromethyl)-ethyl]-6-methyl-4H-pyrrolo[3,2,1-ij]quinolin-4-one, m.p. 242°-243°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH3:17][C:18]1[CH:22]=[C:21]([CH3:23])[NH:20][C:19]=1[CH:24]=O>>[CH3:17][C:18]1[CH:22]=[C:21]([CH3:23])[NH:20][C:19]=1[CH:24]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[NH:11][C:10]1=[O:16]
Reactant: Cc1cc(C)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Product: Cc1cc(C)c(C=C2C(=O)Nc3cccc(-c4ccncc4)c32)[nH]1

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 3,5-dimethyl-1H-pyrrole-2-carbaldehyde to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:17][CH3:18])[CH2:5][CH2:6][O:7][C:8]1[C:9]([N+:14]([O-:16])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1.C(N(CCN[C:35]([C:37]1[CH:46]=[N:45][C:44]2[C:39](=[CH:40][CH:41]=[C:42]([I:47])[CH:43]=2)[N:38]=1)=[O:36])CCOC1C(F)=NC=CC=1)C>>[CH2:17]([N:4]([CH2:3][CH2:2][NH:1][C:35]([C:37]1[CH:46]=[N:45][C:44]2[C:39](=[CH:40][CH:41]=[C:42]([I:47])[CH:43]=2)[N:38]=1)=[O:36])[CH2:5][CH2:6][O:7][C:8]1[C:9]([N+:14]([O-:16])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1)[CH3:18]
Reactant: CCN(CCN)CCOc1cccnc1[N+](=O)[O-]
Reactant: CCN(CCNC(=O)c1cnc2cc(I)ccc2n1)CCOc1cccnc1F
Product: CCN(CCNC(=O)c1cnc2cc(I)ccc2n1)CCOc1cccnc1[N+](=O)[O-]
Yield: 71 %

Procedure:
This compound was prepared, starting from compound 59 (600 mg, 2.36 mmol), according to the procedure developed for compound 10. Reaction time under reflux: 12 h; the purification was performed using column chromatography (Al2O3, CH2C2/EtOH, 99/1, v/v) to give compound 60 (902 mg, 1.68 mmol) as a light sensitive brown oil. Yield 71%; Rf (Al2O3, CH2Cl2/EtOH, 99/1, v/v) 0.46; IR (CCl4) ν 1117, 1289, 1526, 1549, 1683, 2800-3000, 3410 cm−1; 1H NMR (200 MHz, CDCl3) δ 1.08 (t, 3H, J=7.1 Hz), 2.70 (q, 2H, J=7.1 Hz), 2.83 (t, 2H, J=6.1 Hz), 2.99 (t, 2H, J=5.3 Hz), 3.57 (q, 2H, J=6.1 Hz), 4.17 (t, 2H, J=5.3 Hz), 7.36 (dd, 1H, J=4.2, 8.4 Hz), 7.43 (dd, 1H, J=1.7, 8.4 Hz), 7.61 (d, 1H, J=8.8 Hz), 7.94 (dd, 1H, J=1.7, 4.2 Hz), 7.99 (dd, 1H, J=1.8, 8.8 Hz), 8.29 (m, 1H), 8.53 (d, 1H, J=1.8 Hz), 9.57 (s, 1H); ESI-MS m/z 536.9 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([NH:16]C(=O)OC(C)(C)C)[CH3:15])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[ClH:24]>O1CCOCC1.CO>[ClH:24].[ClH:24].[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([NH2:16])[CH3:15])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(N2CCN(C)CC2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@H](N)c1ccc(N2CCN(C)CC2)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
A solution of 1,1-dimethylethyl {(1S)-1-[4-(4-methylpiperazin-1-yl)phenyl]ethyl}carbamate (2 g, 6.3 mmol) and 4N hydrogen chloride in dioxane (5 mL) in methanol (5 mL) was refluxed for 2 min. After cooling to room temperature the mixture was concentrated and rotary evaporated from benzene, and further dried in vacuo to afford 1.7 g, 5.9 mmol (95%) of (S)-1-[4-(4-methylpiperazin-1-yl)phenyl]ethylamine dihydrochloride. MS (EI) for C13H21N3: 220 (MH+).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH2:7])[CH:3]=1.[C:8]1(=O)[O:13][C:11](=[O:12])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12>O1CCOCC1>[CH3:1][C:2]1[NH:6][N:5]=[C:4]([N:7]2[C:11](=[O:12])[C:10]3[C:9](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]2=[O:13])[CH:3]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1cc(N)n[nH]1
Solvent: C1COCCO1
Product: Cc1cc(N2C(=O)c3ccccc3C2=O)n[nH]1
Yield: 50.3 %

Procedure:
In a 100 mL round-bottom flask a mixture of 5-methyl-1H-pyrazol-3-amine (Aldrich, 500 mg, 5.15 mmol) and phthalic anhydride (ALDRICH) (1.07 g, 7.21 mmol) in 1,4-dioxane (30 mL) was stirred at reflux for 25 hours. Reaction was allowed to reach room temperature and the formed precipitate was filtered and washed with EtOH to afford 589 mg of the title compound as a yellowish solid. Filtrate was evaporated to dryness and after washing the residue with EtOH, an additional batch of 331 mg was obtained (total yield: 79%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 12.77 (br s, 1H), 7.87-7.98 (m, 4H), 6.09 (s, 1H), 2.28 (s, 3H). [ES+MS] m/z 228 (MH+).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([N+:10]([O-])=O)[CH:7]=[CH:8][CH:9]=1)[CH:2]=[CH2:3]>C(OCC)(=O)C.[Pd]>[CH2:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[NH2:10])[CH2:2][CH3:3]
Reactant: C=CCc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1cccc(N)c1
Reaction time: 2 h
Yield: 99.5 %

Procedure:
To a suspension of ethyltriphenylphosphonium bromide (22 g) in tetrahydrofuran (150 ml) at -78° C. was added dropwise a solution of n-butyllithium in hexane (59.3 mmol). The mixture was left to warm to room temperature over 30 minutes, then cooled to -78° C. and a solution of 3-nitrobenzaldehyde (7.5 g) in tetrahydrofuran (50 ml) was added dropwise. The reaction was left to warm to room temperature over 1 hour, poured into 2M hydrochloric acid (100 ml) and ethyl acetate (100 ml). The separated aqueous layer was extracted with ethyl acetate, the organic layers were combined and washed with water, saturated sodium bicarbonate (2×50 ml), brine (2×50 ml) and dried over magnesium sulphate. The solvent was removed under reduced pressure and the crude product purified by column chromatography to give 3-(2-propenyl)nitrobenzene (5.72 g). δ(60 MHz, CDCl3) 1.9 (3H,2d, CH3), 5.9 (1 H, m, =CH--CH3), 6.3 (1H, 2d, AR--CH) and 7.3-8.1 (4H, m, ArH). To a solution of the above 3-(2-propenyl)-nitrobenzene (5.7 g) in ethyl acetate (20 ml) was added 10% palladium on carbon (0.57 g). This mixture was hydrogenated at 50 psi for 2 hours at room temperature, filtered through Hyflo and solvent evaporated to yield the crude product which was purified by column chromatography to give 3-propylaniline (4.7 g), δ (60 MHz, CDCl3) 0.9 (3H, t, CH3), 1.5 (2H, m, CH2CH3), 2.4 (2H, t, CH2CH2CH3), 3.4 (2H, bs, NH2) and 6.1 to 7.0 (4H, m, ArH).
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[CH2:3][CH2:4][C:5](=[O:7])[CH3:6].[CH2:9](O)[CH:10]=[CH:11][CH2:12][OH:13].C1CCCCC1>C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C1(C=CC(O)=CC=1)O.O>[CH2:4]([C:5]1([CH3:6])[O:13][CH2:12][CH:11]=[CH:10][CH2:9][O:7]1)[CH2:3][CH:2]([CH3:8])[CH3:1]
Reactant: CC(=O)CCC(C)C
Reactant: OCC=CCO
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: Oc1ccc(O)cc1
Solvent: C1CCCCC1
Solvent: O
Product: CC(C)CCC1(C)OCC=CCO1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
To a one liter flask equipped with heating jacket, agitator and condenser fitted with a Dean-Stark trap was charged 136 grams (1.2 mole) 5-methyl-2-hexanone, 88 grams (1.0 mole) 2-butene-1,4-diol, 160 grams cyclohexane, 2 grams citric acid and 0.3 grams hydroquinone. The mixture was heated with vigorous agitation at reflux (87°- 97°C.) until water no longer continued to be distilled from the reaction mixture (24 hours). The reaction mixture was cooled to room temperature and the citric acid neutralized by washing the reaction mixture with a 5% aqueous solution of sodium hydroxide and then with water. The reaction mixture was then distilled to remove the cyclohexane and the oil vacuum distilled to obtain 152 grams (83% of theoretical) of 4,7-dihydro-2-isopentyl-2-methyl-1,3-dioxepin having a boiling point of 94°C. at a pressure of 9.0 millimeters of mercury (refractive index, ND20 = 1.4523). Analysis for carbonyl content by IR showed 0.0% carbonyl and VPC analysis showed the compound to have a purity of 97.4%.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][NH2:27]>>[C:1]([NH:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22][OH:21])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: NCCNCCO
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCCCC(=O)NCCNCCO

Procedure:
The dehydration condensation reaction of stearic acid with N-hydroxyethyl ethylene diamine was carried out, and the reaction product was hydrolyzed and distilled to give N-stearoyl-N′-hydroxyethyl ethylene diamine. It was dissolved in ethanol, and 1.1-fold equivalents (based on the amine) of formalin was added dropwise thereto under reflux, then 1.1-fold equivalents (based on the amine) of formic acid was added dropwise thereto, and the mixture was aged for 5 hours. The reaction product was further quaternarized with methyl chloride to give N-stearoylaminoethyl-N-hydroxyethyl-N,N-dimethyl ammonium chloride.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[C:33](Cl)(=[O:36])[CH:34]=[CH2:35]>C1COCC1>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:36])[CH:34]=[CH2:35])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: C=CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(N)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccc(S(=O)(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.4 %

Procedure:
Diisopropylethylamine (0.09 ml, 0.5 mmol) was added in one portion to a stirred solution of 4-(4-Amino-benzenesulfonyl)-piperidine-1-carboxylic acid tert-butyl ester (0.11 g, 0.33 mmol) in THF (3 ml) at room temperature. To this mixture was added acryloyl chloride (0.03 ml, 0.5 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time, the mixture was concentrated under vacuum and the resulting residue was purified by column chromatography (elution: 40% heptane, 60% ethyl acetate) to give the title compound (0.02 g, 17% yield) as a white solid.
Reaction SMILES: [O:1]=[S:2]1(=[O:40])[CH2:6][CH2:5][CH:4]=[C:3]1[C:7]1[CH:39]=[CH:38][C:10]2[NH:11][C:12]([C:17]3[C:18](=[O:37])[N:19]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[C@@H:20]4[C@H:25]([C:26]=3[OH:27])[C@@H:24]3[CH2:28][C@H:21]4[CH2:22][CH2:23]3)=[N:13][S:14](=[O:16])(=[O:15])[C:9]=2[CH:8]=1>CO.[Pd]>[O:40]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:39]=[CH:38][C:10]2[NH:11][C:12]([C:17]3[C:18](=[O:37])[N:19]([CH2:29][C:30]4[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=4)[C@@H:20]4[C@H:25]([C:26]=3[OH:27])[C@@H:24]3[CH2:28][C@H:21]4[CH2:22][CH2:23]3)=[N:13][S:14](=[O:15])(=[O:16])[C:9]=2[CH:8]=1
Reactant: O=C1C(C2=NS(=O)(=O)c3cc(C4=CCCS4(=O)=O)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Agent: [Pd]
Solvent: CO
Product: O=C1C(C2=NS(=O)(=O)c3cc(C4CCCS4(=O)=O)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
(1R,2S,7R,8S)-5-[7-(1,1-Dioxo-4,5-dihydro-1H-1λ6-thiophen-2-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl]-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (prepared as described in Example 20, 30 mg, 0.05 mmol) was dissolved in methanol (15 mL) and 5% palladium on charcoal (100 mg) was added. The flask was degassed and backfilled with hydrogen gas via balloon. The mixture was stirred at 25° C. for 16 h. The mixture was passed through a plug of Celite, rinsed with 10% methanol/dichloromethane, and the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 150×21.2 mm, 5 micron, 30%-95% in 7 min @30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, (1R,2S,7R,8S)-5-[7-(1,1-dioxo-tetrahydro-1λ6-thiophen-2-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl]-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (26 mg, 0.044 mmol, 86%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.19 (2H, m), 1.40-1.60 (4H, m), 2.12 (1H, m), 2.67 (1H, m), 2.36 (1H, m), 2.50 (1H, m), 2.65 (1H, m), 3.03 (1H, m), 3.23 (1H, m), 3.32 (1H, m), 3.53 (1H, d, J=10.0 Hz), 4.42 (1H, d, J=15.2 Hz), 4.56 (1H, dd, J=11.6, 6.8 Hz), 4.97 (1H, d, J=15.6 Hz), 7.14 (2H, m), 7.33 (2H, m), 7.58 (1H, d, J=8.8 Hz), 7.69 (1H, dd, J=8.8, 2.4 Hz), 7.82 (1H, d, J=2.4 Hz); LC-MS (ESI) calcd for C28H28FN3O6S2 585.14, found 586.3 [M+H+].
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[CH:22]=[C:21]([OH:25])[CH:20]=[CH:19][C:18]=2[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][C@@H:16]2[F:26])([CH3:14])[C:12](=[O:27])[CH2:11][CH2:10]1.[I-:28].[Na+].O>CC(CC)=O>[F:26][C@H:16]1[CH2:15][C@@:13]2([CH3:14])[C@@H:9]([CH2:10][CH2:11][C:12]2=[O:27])[C@H:8]2[C@H:17]1[C:18]1[CH:19]=[CH:20][C:21]([OH:25])=[CH:22][C:23]=1[CH2:24][C@H:7]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][I:28]
Reactant: [I-]
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCl)[C@H]3[C@@H]1CCC2=O
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: O
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCI)[C@H]3[C@@H]1CCC2=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 110.3 %

Procedure:
5.0 g of 7α-(5-chloropentyl)-11β-fluoro-3-hydroxy-estra-1,3,5(10)-trien-17-one is dissolved in 80 ml of ethyl methyl ketone, mixed with 5.7 g of sodium iodide and stirred overnight at a bath temperature of 90° C. For working-up, the reaction mixture is cooled to room temperature, stirred into water, extracted 3 times with ethyl acetate, washed with common salt solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. 6.8 g of 11β-fluoro-3-hydroxy-7α-(5-iodopentyl)-estra-1,3,5(10)-trien-17-one is obtained as crude product, which is used without further purification in the next stage.