Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:20]([CH3:21])[CH:19]=[CH:18][C:5]2=[N:6][C:7]=1[C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9].[O:22]1[CH2:27][CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH2:24][CH2:23]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:22]1[CH2:23][CH:24]=[C:25]([C:2]2[CH:3]=[C:4]3[N:20]([CH3:21])[CH:19]=[CH:18][C:5]3=[N:6][C:7]=2[C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])[CH2:26][CH2:27]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccn(C)c2cc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccn(C)c2cc1C1=CCOCC1
Temperature: 90 °C

Procedure:
To a 20 mL microwave vial were added (S)-tert-butyl (1-(6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)carbamate (1 g, 2.8 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.890 g, 4.23 mmol), PdCl2(dppf) (0.207 g, 0.282 mmol) and cesium carbonate (1.84 g, 5.65 mmol) in dioxane (12 mL) and water (2 mL). The resulting brown suspension was heated in a microwave reactor at 90° C. on high absorbance for 1 hour. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NH4Cl (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated. The product was purified using silica gel column chromatography (12 g, 2:8 to 8:2 EtOAc/hexane) to give the title compound as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99-1.13 (m, 9 H), 1.25-1.38 (m, 12 H), 3.74-3.97 (m, 7 H), 4.16-4.26 (m, 2H), 4.90-5.05 (m, 1 H), 5.68-5.77 (m, 1 H), 6.47-6.55 (m, 1 H), 6.76-6.87 (m, 1 H), 7.59 (s, 2 H); ESI-MS m/z [M+H]+ calc'd for C20H27N3O3, 358; found 358.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH2:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NOCc1ccccc1
Reactant: ClCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCOC1CCCCO1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
To a stirred solution of N-tert-butyloxycarbonyl-O-benzylhydroxylamine 28 (5.79 g, 25.96 mmol) in dry DMF (50 ml) was added NaH (60%, 1.2 g, 30 mmol) slowly during 15 min period under argon atmosphere at 0° C. The reaction was allowed to stir at 0° C. for 30 min and at room temperature for 1 h. 1-Chloro-2-(tetrahydropyranyl)oxy-ethane 29 (4.95 g, 30 mmol) was added and the reaction mixture was heated at 80° C. for 12 h. The reaction was cooled and evaporated to dryness. The residue was suspended in water (50 ml), pH of the solution adjusted to 7 and extracted in EtOAc (150 ml). The EtOAc extract was washed with water and brine, dried and evaporated to dryness. The residue was purified by flash chromatography over silica gel using hexane→CH2Cl2 as the eluent. The required fractions were collected and evaporated to give 6.0 g (66%) of an oily product. 1HNMR (CDCl3): δ1.48 (s, 9H, Boc), 1.49-1.84 (m, 6H, 3.CH2), 3.48-3.70 (m, 4H, 2.CH2), 3.86 (m, 2H, CH2), 4.60 (t, 1H, CH), 4.84 (s, 2H, CH2Ph) and 7.32-7.42 (m, 5H, Ph).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:9][C:10]1([CH3:19])[CH2:15][CH:14]([NH2:16])[CH2:13][C:12]([CH3:18])([CH3:17])[NH:11]1.C(O)CCC>O.C(Cl)Cl>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:16][CH:14]2[CH2:15][C:10]([CH3:19])([CH3:9])[NH:11][C:12]([CH3:18])([CH3:17])[CH2:13]2)=[CH:6][CH:7]=1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: Clc1ccc(Cl)nn1
Solvent: CCCCO
Solvent: ClCCl
Solvent: O
Product: CC1(C)CC(Nc2ccc(Cl)nn2)CC(C)(C)N1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A mixture of 3,6-dichloropyridazine (6.26 g, 42 mmol) and 2,2,6,6-tetramethylpiperidin-4-amine (14.7 mL, 84 mmol) was stirred at 120° C. for 1 h, neat. To this crude mixture was added n-butanol (40 mL), and the reaction was stirred at 120° C. for 1 h. The crude reaction mixture was cooled to room temperature and diluted in water and CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated. The crude material was recrystallized from CH3CN to give 6-chloro-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine, Intermediate 1-2 (7.3 g) as an off-white solid. LCMS Rt=1.10 min (condition B), MS (M+1)=269.2. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.08 (d, J=9.3 Hz, 1H), 6.54 (d, J=9.3 Hz, 1H), 4.53 (d, J=7.6 Hz, 1H), 4.05-4.26 (m, 1H), 1.98 (dd, J=12.6, 3.8 Hz, 2H), 1.22 (s, 6H), 1.08 (s, 6H), 0.93 (apparent t, J=12.1 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([O:10][C:11]2[N:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[N:12]=2)[CH:5]=[CH:4][CH:3]=1.[Mn]([O-])(=O)(=O)=[O:22].[K+].O.O.O.O.O.O.O.OP([O-])([O-])=O.[Na+].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(C)=O.O>[Cl:1][C:2]1[C:7]([C:8]([OH:22])=[O:9])=[C:6]([O:10][C:11]2[N:12]=[C:13]([O:19][CH3:20])[CH:14]=[C:15]([O:17][CH3:18])[N:16]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COc1cc(OC)nc(Oc2cccc(Cl)c2C=O)n1
Agent: O=P([O-])([O-])O
Agent: O=S([O-])([O-])=S
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(OC)nc(Oc2cccc(Cl)c2C(=O)O)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.5 %

Procedure:
To stirred solution of 9.6 grams (0.033 mole) of 6-chloro-2-(4,6-dimethoxypyrimidin-2-yloxy)benzaldehyde in 260 mL of acetone was added dropwise a solution of 7.7 grams (0.049 mole) of potassium permanganate and 6.6 grams (0.024 mole) of sodium phosphate dibasic heptahydrate in 105 mL of water while maintaining the reaction mixture temperature at 20°-25° C. Upon completion of addition, the reaction mixture was stirred at ambient temperature for 18 hours. After this time sodium thiosulfate was added to the reaction mixture to destroy excess permanganate. The reaction mixture was then filtered through diatomaceous earth. The filtrate was cooled and acidified to a pH of 3-4 with aqueous 10% hydrochloric acid. The mixture was extracted with two 50 mL portions of methylene chloride. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was crystallized from methylene chloride and carbon tetrachloride to yield 10.0 grams of 6-chloro-2 -(4,6-dimethoxypyrimidin-2-yloxy)benzoic acid. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Cl:23][C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:25]=1[N:33]=[C:34]=[O:35]>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:25]=1[NH:33][C:34]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:35]
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc([N+](=O)[O-])cc4Cl)cc3)c2cc1OC
Yield: 99 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (104 mg) was dissolved in toluene (10 ml) with heat, 2-chloro-4-nitrophenyl isocyanate (150 mg) was added, and the admixture was refluxed with heat for 10 minutes. The separated crystals were filtered and then washed with toluene to obtain 172 mg of the title compound (yield: 100%).
Reaction SMILES: FC(F)(F)C(O)=O.O.[Cl:9][CH:10]([Cl:39])[C:11]([N:13]1[C@H:17]([CH2:18][F:19])[C@@H:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[CH:28][C:29]([C:32]4([F:36])[CH2:35][O:34][CH2:33]4)=[N:30][CH:31]=3)=[CH:22][CH:21]=2)[O:15]C1(C)C)=[O:12]>C(Cl)Cl>[Cl:39][CH:10]([Cl:9])[C:11]([NH:13][C@H:17]([CH2:18][F:19])[C@@H:16]([C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[N:30][C:29]([C:32]3([F:36])[CH2:33][O:34][CH2:35]3)=[CH:28][CH:27]=2)=[CH:24][CH:25]=1)[OH:15])=[O:12]
Reactant: CC1(C)O[C@H](c2ccc(-c3ccc(C4(F)COC4)nc3)cc2)[C@@H](CF)N1C(=O)C(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O=C(N[C@H](CF)[C@H](O)c1ccc(-c2ccc(C3(F)COC3)nc2)cc1)C(Cl)Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Trifluoroacetic acid (0.932 mL, 12.1 mmol) and a drop of water is added to a stirred solution of the product of step 2, Example 17 (380.0 mg, 0.806 mmol) in methylene chloride (5.0 mL) at 0° C. and the reaction mixture is stirred at this temperature for 10 minutes before being warmed to room temperature. After 4 hours, the solution is concentrated then diluted with methylene chloride at 0° C., quenched with saturated sodium hydrogen carbonate solution, and the aqueous layer extracted with methylene chloride. The combined organic layers were washed with brine, dried, and concentrated. The title compound is obtained (55.1 mg): 1H NMR (300 MHz, DMSO) δ 4.21-4.32 (m, 2.5 H), 4.42-4.47 (m, 0.5 H), 4.54-4.59 (m, 0.5 H), 4.70-4.75 (m, 0.5 H), 4.88-4.99 (m, 3H), 5.03-5.14 (m, 2H), 6.00 (d, 1H), 6.53 (s, 1H), 7.50 (d, 2H), 7.63 (d, 1H), 7.74 (d, 2H), 8.17-8.20 (dd, 1H), 8.62 (d, 1H), 8.99-9.03 (m, 1H). MS (ESI+) m/z 431.1, 433.0, and 435.0 [M+H].
Reaction SMILES: Br[C:2]1[C:3]([F:25])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:24]=1.[CH3:26][C:27]1[O:31][N:30]=[C:29]([C@:32]([OH:36])([C:34]#[CH:35])[CH3:33])[CH:28]=1>>[F:25][C:3]1[C:2]([C:35]#[C:34][C@@:32]([OH:36])([C:29]2[CH:28]=[C:27]([CH3:26])[O:31][N:30]=2)[CH3:33])=[CH:24][C:6]2[C:7]3[N:8]([C:12]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: NC(=O)c1nc2n(c1CN1CCCC1)CCOc1cc(F)c(Br)cc1-2
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Product: Cc1cc([C@](C)(O)C#Cc2cc3c(cc2F)OCCn2c-3nc(C(N)=O)c2CN2CCCC2)no1
Yield: 28 %

Procedure:
10-bromo-9-fluoro-3-(pyrrolidin-1-ylmethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol similarly to as described in General Procedure F with non-critical modifications to afford 26 mg (28%) of 9-fluoro-10-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]-3-(pyrrolidin-1-ylmethyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide. M+1=480.3.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20]N1C(=O)CCC1=O>CN(C=O)C>[CH2:1]([NH:8][C:9]1[S:10][C:11]([Cl:20])=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: c1ccc(CNc2nc(-c3ccccn3)cs2)cc1
Solvent: CN(C)C=O
Product: Clc1sc(NCc2ccccc2)nc1-c1ccccn1
Temperature: 25 °C

Procedure:
A solution of N-benzyl-4-(pyridin-2-yl)thiazol-2-amine (60 mg, 0.23 mmol) in DMF (2 mL) was cooled to 0° C. and treated with N-chlorosuccinimide (33 mg, 0.25 mmol), and the reaction mixture was allowed to warm to room temperature. The solvent was evaporated, and the product was purified on reverse phase HPLC to produce N-benzyl-5-chloro-4-(pyridin-2-yl)thiazol-2-amine. MS (Q1) 302.2 (M)+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11].C(NCC)C.C(O)(=O)C>C(O)C>[NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:12]([C:10]#[N:11])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC#N
Reactant: Nc1ccc(C=O)cc1
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCNCC
Product: CCOC(=O)C(C#N)=Cc1ccc(N)cc1
Yield: 83.1 %

Procedure:
36 g (0.3 mol) of para-aminobenzaldehyde are suspended in 300 ml of ethanol. 33.9 g (0.3 mol) of ethyl cyanoacetate and a mixture of 0.375 ml of diethylamine and 1.125 ml of acetic acid, as catalyst, are added to the suspension. The reaction mixture is refluxed for 2 hours, left to cool and then crystallized. After separating out the crystals by filtration and drying, 53.9 g (83% yield) of ethyl 3-(4-aminophenyl)-2-cyanoacrylate are obtained in the form of orange-coloured crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([OH:16])[CH2:13][CH:12]2[CH2:14][CH2:15][CH:5]1[C:6]1[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=1.[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18].CCN(CC)CC>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[OH:16][C@@:4]1([CH2:3][CH2:2][O:1][S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:13][C@H:12]2[CH2:14][CH2:15][C@@H:5]1[C:6]1[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCCC1(O)CC2CCC1c1ccccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC[C@]2(O)C[C@H]3CC[C@@H]2c2ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
A mixture of 2.0 g of rac-(1R*,8R*,9R*)-9-(2-hydroxy-ethyl)-tricyclo[6.2.2.02,7]dodeca-2,4,6-trien-9-ol, 1.9 g of TsCl, 1.5 mL of NEt3 and 0.22 g of DMAP in 120 mL of toluene was stirred overnight at rt. The reaction mixture was quenched with water, the organic phase was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by CC with Hept/EtOAc (1:1) to yield 2.7 g of the desired compound as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([OH:30])[CH:24]=3)[C@@H:14]([CH3:32])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:40][CH2:41][C:42]([CH3:48])([CH3:47])[C:43]([O:45][CH3:46])=[O:44]>CN(C=O)C>[C:9]([N:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C@H:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([C:22]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([CH:24]=2)[O:30][CH2:40][CH2:41][C:42]([CH3:48])([CH3:47])[C:43]([O:45][CH3:46])=[O:44])=[O:31])[C@@H:14]([CH3:32])[CH2:13]1)(=[O:11])[CH3:10]
Reactant: COC(=O)C(C)(C)CCBr
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)c(O)c2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)CCOc1cc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
N-(4-chlorophenyl)-N-[(2S,4R)-1-(4-fluoro-3-hydroxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide (476 mg, 1.05 mmol) was dissolved in DMF at room temperature and Cs2CO3 (854 mg, 2.63 mmol) was added. Methyl 4-bromo-2,2-dimethylbutanoate (702 mg, 1.58 mmol) was added and the reaction was stirred at r.t. overnight. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography (hexanes-ethyl acetate system) to afford methyl 4-(5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}-2-fluorophenoxy)-2,2-dimethylbutanoate (286 mg, 52%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][C:14]=2[CH3:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]1([S:27]([N:30]2[C:38]3[C:33](=[CH:34][C:35]([F:39])=[CH:36][CH:37]=3)[C:32](Br)=[CH:31]2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19][C:32]3[C:33]4[C:38](=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=4)[N:30]([S:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)(=[O:29])=[O:28])[CH:31]=3)=[CH:15][C:14]=2[CH3:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(S)ccc1C1CCN(C(=O)OC(C)(C)C)C1
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c2cc(F)ccc21
Product: Cc1cc(Sc2cn(S(=O)(=O)c3ccccc3)c3ccc(F)cc23)ccc1C1CCN(C(=O)OC(C)(C)C)C1

Procedure:
3-(4-Mercapto-2-methyl-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester was reacted with 1-benzenesulfonyl-3-bromo-5-fluoro-1H-indole using the procedure of step 1 of Example 3 to provide 3-[4-(1-Benzenesulfonyl-5-fluoro-1H-indol-3-ylsulfanyl)-2-methyl-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [OH:1][C@H:2]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:21]2[CH2:20][C@@H:19]([OH:26])[C@@:18]2([CH3:27])[C@:8]3([OH:28])[CH2:9][CH2:10][C@@H:11]2[C:12]2(OCCO2)[CH3:13])[CH2:3]1>C(O)(=O)C>[OH:1][C@H:2]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:21]2[CH2:20][C@@H:19]([OH:26])[C@@:18]2([CH3:27])[C@:8]3([OH:28])[CH2:9][CH2:10][C@@H:11]2[CH2:12][CH3:13])[CH2:3]1
Reactant: CC1([C@H]2CC[C@]3(O)[C@@H]4CC=C5C[C@@H](O)CC[C@]5(C)[C@H]4C[C@@H](O)[C@]23C)OCCO1
Solvent: CC(=O)O
Product: CC[C@H]1CC[C@]2(O)[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3C[C@@H](O)[C@]12C
Yield: 93.4 %

Procedure:
The ethylenedioxypregnene (25) (250 mg, 0,64 mmol) is dissolved in acetic acid (13,4 ml) and water which after freeze drying affords the trihydroxy steroid (15) (200 mg, 89%), m.p.: 228°-235° C. (lit 225°-235° C.), M+ 348, [αD]20+35° (lit [αD]20+29°).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].I[CH2:21][C:22]([F:25])([F:24])[F:23].C([O-])([O-])=O.[K+].[K+]>>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: FC(F)(F)CI
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C)C(=O)N(CC(F)(F)F)c2cc([N+](=O)[O-])c(N)cc21
Yield: 58 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (5 g) is alkylated in a high pressure reaction vessel using 2-iodo-1,1,1-trifluoro-ethane (5.7 ml; 38 mmol) and K2CO3 (5.25 g; 38 mmol) at 50° C. for 14 days. After aqueous work-up and purification by RP chromatography the pure material (4 g) is de-acetylated in MeOH (150 ml) using DBU (3.6 ml) at reflux. After aqueous work-up 5-amino-3,3-dimethyl-6-nitro-1-(2,2,2-trifluoro-ethyl)-1,3-dihydro-indol-2-one (3,34 g) is obtained and used without further purification.
Reaction SMILES: CS(OCC[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][C@@H:20]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[C:19]4[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:36][O:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][N:43]([CH2:46][CH2:47]N)[CH2:42][CH2:41]1>C(N(CC)CC)C>[F:31][C:28]1[CH:27]=[CH:26][C:25]([C@H:20]2[C:19]3[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=3[C:17]3[N:16]=[C:15]([NH:14][C:11]4[CH:10]=[CH:9][C:8]([CH2:47][CH2:46][N:43]5[CH2:44][CH2:45][N:40]([CH2:39][CH2:38][O:37][CH3:36])[CH2:41][CH2:42]5)=[CH:13][CH:12]=4)[N:24]=[CH:23][C:22]=3[CH2:21]2)=[CH:30][CH:29]=1
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccc(F)cc2)C3)cc1
Reactant: COCCN1CCN(CCN)CC1
Solvent: CCN(CC)CC
Product: COCCN1CCN(CCc2ccc(Nc3ncc4c(n3)-c3ccccc3[C@H](c3ccc(F)cc3)C4)cc2)CC1

Procedure:
This was synthesized by using (S)-4-(6-(4-fluorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate, 2-(4-(2-methoxyethyl)piperazin-1-yl)ethanamine and triethylamine as described in general procedure 2 to afford the desired product. M.p.=195-198° C.; 1H NMR (CDCl3/DMSO-d6) 400 MHz δ 8.37 (d, J=7.0 Hz, 1H), 8.03, (s, 1H), 7.73 (d, J=8.2 Hz, 2H), 7.63 (s, 3H), 7.54-7.57 (m, 2H), 7.34-7.37 (d, J=7.0 Hz, 1H) 1H), 8.01 (brs, 1H), 7.69 (d, J=6.6 Hz, 2H), 7.58-7.59 (m, 2H), 7.35 (d, J=8.6 Hz, 2H), 7.12 (d, J=7.0 Hz, 1H), 7.05-7.08 (m, 2H), 7.01, 7.04 (m, 2H), 4.43 (t, J=7.0 Hz, 1H), 3.89-3.91 (m, 7H), 3.39 (s, 5H), 3.28-3.30 (m, 2H), 2.02 (s, 2H). LCMS m/e 538 [M+H].
Reaction SMILES: CN(C)C=O.Cl.Cl[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[NH2:16][C:17](=[O:49])[C:18]([C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[O:29][CH2:30][C:31]([OH:33])=[O:32])[N:22]([CH2:34][C:35]2[CH:36]=[C:37]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:38]=[CH:39][CH:40]=2)[C:21]=1[CH2:47]C)=[O:19].[Na]>O>[NH2:16][C:17](=[O:49])[C:18]([C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[O:29][CH2:30][C:31]([O:33][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:32])[N:22]([CH2:34][C:35]2[CH:36]=[C:37]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:38]=[CH:39][CH:40]=2)[C:21]=1[CH3:47])=[O:19]
Reactant: ClCCN1CCOCC1
Reactant: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cccc2n1Cc1cccc(-c2ccccc2)c1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)OCCN3CCOCC3)cccc2n1Cc1cccc(-c2ccccc2)c1
Temperature: 60 °C

Procedure:
In a flask containing 10 ml of dimethylformamide is added with stirring 133 mg. of 4-(2-chloroethyl)morpholine hydrochloride (available from Aldrich Chemical Co., Milwaukee, Wis. USA, Item No. C4,220-3) and 231 mg. of CsCO3 and 300 mg. of ((3-(2-amino-1,2-dioxoethyl)-1-((1,1′-biphenyl)-3-ylmethyl)-2-ethyl-1H-indol-4-yl)oxy)acetic acid, sodium salt. The slurry is heated to 60° C. until a solution formed. Heating is continued overnight until reaction is complete. 20 ml of H2O is added to the flask and the organic soluble phase is extracted with three 20 ml. portions of ethyl acetate. The ethyl acetate solution is washed with water and dried over Na2SO4.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)=O)(C)(C)C.[C:44](Cl)(=[O:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[C:45]1([C:44]([NH:8][C@@H:9]2[CH2:13][C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@@H:11]([CH2:20][N:21]3[CH2:22][CH2:23][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=4)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:25][CH2:26]3)[CH2:10]2)=[O:51])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](NC(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](NC(=O)c3ccccc3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(R)-((t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 34 in Step A and benzoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [CH2:1]([N:3](CC)[CH2:4]C)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O[CH2:20][C:21]1[N:26]=[CH:25][C:24]2[CH:27]=[CH:28][O:29][C:23]=2[CH:22]=1>C(Cl)Cl>[CH3:1][N:3]([CH2:20][C:21]1[N:26]=[CH:25][C:24]2[CH:27]=[CH:28][O:29][C:23]=2[CH:22]=1)[CH3:4]
Reactant: OCc1cc2occc2cn1
Reactant: CCN(CC)CC
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: CN(C)Cc1cc2occc2cn1
Reaction time: 0.25 h
Yield: 55.5 %

Procedure:
To a solution of triethylamine (3.45 mL, 24.7 mmol) in methylene chloride (16 mL) under a nitrogen atmosphere and cooled below 5° C. was added p-toluenesulfonyl chloride (4.65 g, 24.4 mmol) in one portion. After stirring the mixture for 15 minutes, a solution of 6-hydroxymethylfuro[3,2-c]pyridine (2.68 g, 18 mmol) in methylene chloride (18 mL) was added dropwise. By tlc the reaction was complete in 6-8 hours. Dimethylamine gas was bubbled over the reaction surface until product formation was complete. The reaction solution was washed with water and the product extracted into dilute hydrochloric acid. The acidic aqueous extract was made basic with sodium hydroxide solution and the product extracted into diethyl ether. The ethereal solution was dried over anhydrous sodium sulfate, filtered through a pad of charcoal and evaporated to give an oil (1.76 g). The oil was distilled under vacuum to give 1.56 g (49% yield) of pure product, bp: 93°-94° C./1.6 mm Hg. Upon standing the product crystallized, mp: 42°-44° C.