Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([O:10][CH3:11])[N:5]=[CH:4][CH:3]=1.CC(=CC)C.O.Cl([O-])=[O:19].[Na+]>CC(O)(C)C>[I:1][C:2]1[C:7]([C:8]([OH:19])=[O:9])=[C:6]([O:10][CH3:11])[N:5]=[CH:4][CH:3]=1
Reactant: [O-][Cl+][O-]
Reactant: COc1nccc(I)c1C=O
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1nccc(I)c1C(=O)O
Reaction time: 0.08 h

Procedure:
To a solution of 4-iodo-2-methoxynicotinaldehyde (1 g, 3.58 mmol) in t-BuOH (6 mL), cooled at 25° C., is added 2-methyl-2-butene (6 mL, 2 M solution), Na2HPO4 (1.2 g) and water (3 mL). The reaction mixture is stirred for 5 minutes and sodium chlorite (800 mg, 8.9 mmol) is added slowly. Stirring of the mixture is continued until the aldehyde is completely consumed (3 hours, monitored by LCMS). The reaction is quenched with aq. formic acid. The mixture is partitioned between ethyl acetate (100 mL) and the organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated. The white powder was used for the next reaction without any further purification. 1H NMR 400 MHz (DMSO-d6) δ 10.06 (s, 1H), 7.89 (d, 1H, J=5.6 Hz), 7.48 (d, 1H, J=5.6 Hz), 3.87 (s, 1H); MS m/z 294.1 (M+1). MS m/z 280.01 (M+1).
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[NH:26][N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.Cl.Cl.[CH3:29][O:30][C@@H:31]1[CH2:35][NH:34][CH2:33][C@H:32]1[NH2:36]>>[NH2:36][C@H:32]1[C@H:31]([O:30][CH3:29])[CH2:35][N:34]([C:2]2[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)=[CH:20][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=3)=[O:7])=[CH:4][N:3]=2)[CH2:33]1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccn[nH]2)c1
Reactant: CO[C@@H]1CNC[C@H]1N
Agent: Cl
Product: CO[C@@H]1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2ccn[nH]2)C[C@H]1N

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 48 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1H-pyrazol-5-yl)nicotinamide (Stage 48.1) and trans-4-methoxypyrrolidin-3-amine dihydrochloride (Stage 78.1) to afford a beige solid. HPLC (Condition 7) tR=5.797 min, UPLC-MS (Condition 3) tR=0.81 min, m/z=479.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.86-2.98 (m, 1H) 3.06-3.19 (m, 1H) 3.21 (s, 3H) 3.25-3.43 (m, 2H) 3.43-3.59 (m, 2H) 6.32-6.46 (m, 1H) 7.32 (d, J=8.60 Hz, 2H) 7.50-7.92 (m, J=8.99 Hz, 3H) 8.03 (s, 1H) 8.62-8.86 (m, 1H) 10.18 (s, 1H) 12.72-13.25 (m, 1H).
Reaction SMILES: [N:1]1([C:5]2[N:10]=[C:9]([CH2:11][N:12]3[C@@H:16]([CH3:17])[C@@H:15]([C:18]4[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=4)[O:14][C:13]3=[O:32])[C:8]([C:33]3[C:34]([CH3:47])=[C:35](/[CH:41]=[CH:42]/[C:43]([O:45]C)=[O:44])[CH:36]=[CH:37][C:38]=3[O:39][CH3:40])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[N:1]1([C:5]2[N:10]=[C:9]([CH2:11][N:12]3[C@@H:16]([CH3:17])[C@@H:15]([C:18]4[CH:19]=[C:20]([C:28]([F:30])([F:29])[F:31])[CH:21]=[C:22]([C:24]([F:25])([F:27])[F:26])[CH:23]=4)[O:14][C:13]3=[O:32])[C:8]([C:33]3[C:34]([CH3:47])=[C:35]([CH2:41][CH2:42][C:43]([OH:45])=[O:44])[CH:36]=[CH:37][C:38]=3[O:39][CH3:40])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)/C=C/c1ccc(OC)c(-c2ccc(N3CCC3)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ccc(CCC(=O)O)c(C)c1-c1ccc(N2CCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 45 °C
Reaction time: 1.5 h

Procedure:
To a solution of methyl (2E)-3-{3-[6-(azetidin-1-yl)-2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)pyridin-3-yl]-4-methoxy-2-methylphenyl}prop-2-enoate (118 mg, 0.178 mmol) in methanol (2371 μl) was added palladium on carbon (10%) (59 mg, 0.178 mmol). This mixture was placed under a balloon of hydrogen gas and purged three times with vacuum, then allow to stir at 45° C. for 1.5 hours. LC/MS indicated complete conversion to desired product. The mixture was then diluted with filtered though a plug of Celite®. The residue was concentrated to furnish the desired product as a 53/47 mixture of atropisomers. To a solution of this mixture (98 mg, 0.147 mmol) in dioxane (1996 μl) and water (499 μl) was added lithium hydroxide (35.3 mg, 1.472 mmol). The reaction was stirred at room temp for 5 hours until complete. The mixture was then concentrated in vacuo and purified on reverse phase HPLC (C-18 column, 0-90% acetonitrile in water). The pure mixture of atropisomers was then separated on a Chiral SFC (Chiralcel AD-H column, 10% EtOH in CO2). To provide both atropisomers. Atropisomer A: Mass spectrum (ESI) 652.3 (M+1). 1H NMR (500 MHz, CDCl3) (atropisomers) δ 7.85 (s, 1H), 7.73 (s, 2H), 7.19 (d, J=8.4 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.32 (d, J=8.4 Hz, 1H), 5.69 (d, J=8.7 Hz, 1H), 4.55 (m, 1H), 4.43 (d, J=15.8 Hz, 1H), 4.10 (m, 4H), 3.72 (m, 1H), 3.65 (s, 3H), 2.97 (m, 2H), 2.64 (t, J=7.6 Hz, 2H), 2.44 (t, J=7.2 Hz, 2H), 2.00 (s, 3H), 0.71 (d, J=6.6 Hz, 3H). Atropisomer B: Mass spectrum (ESI) 652.3 (M+1). 1H NMR (500 MHz, CDCl3) (atropisomers) δ 7.84 (s, 1H), 7.68 (s, 2H), 7.20 (d, J=7.9 Hz, 1H), 7.16 (d, J=8.5 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 6.32 (d, J=7.6 Hz, 1H), 5.51 (d, J=8.0 Hz, 1H), 4.62 (d, J=15.9 Hz, 1H), 4.22 (m, 1H), 4.09 (m, 4H), 3.73 (m, 1H), 2.95 (m, 2H), 2.64 (t, J=7.5 Hz, 2H), 2.43 (t, J=7.2 Hz, 2H), 2.02 (s, 3H), 0.68 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([NH:18][C:19]([C@@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][N:22]2[C:27]2[O:28][C:29]3[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=3[N:31]=2)=[O:20])[CH2:15]1)(C1C=CC=CC=1)[C:2]1C=CC=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[O:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=[C:27]1[N:22]1[CH2:23][CH2:24][CH2:25][CH2:26][C@H:21]1[C:19]([NH:18][CH:16]1[CH2:17][N:14]([CH2:1][CH3:2])[CH2:15]1)=[O:20]
Reactant: O=C(NC1CN(C(c2ccccc2)c2ccccc2)C1)[C@@H]1CCCCN1c1nc2ccccc2o1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCN1CC(NC(=O)[C@@H]2CCCCN2c2nc3ccccc3o2)C1
Reaction time: 18 h
Yield: 43.9 %

Procedure:
20% w/w Palladium hydroxide on carbon (31 mg) was added to a solution of (2S)-N2-(1-benzhydryl-3-azetanyl)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxamide (120 mg) [see Example 28] in ethanol (5 ml). The reaction mixture was hydrogenated for 18 hours at 414 kPa (60 p.s.i.), after which time additional 20% w/w palladium hydroxide on carbon (32 mg) was added and the mixture hydrogenated for a further 72 hours. The catalyst was then filtered off and washed with ethanol and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0 changing to 90:10, by volume, dichloromethane:methanol in 2% increments, to afford (2S)-1-(1,3-benzoxazol-2-yl)-N2-(1-ethyl-3-azetanyl)-2-piperidinecarboxamide (37.1 mg) as a foam.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[CH2:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.[CH3:16][Si:17](Cl)([CH3:19])[CH3:18]>CCCCCC>[CH3:16][Si:17]([CH3:19])([CH3:18])[CH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15]([Si:17]([CH3:19])([CH3:18])[CH3:16])=[C:7]1[CH3:6]
Reactant: C[Si](C)(C)Cl
Reactant: CC1=Cc2ccccc2C1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CC1=C([Si](C)(C)C)c2ccccc2C1[Si](C)(C)C
Reaction time: 10 h
Yield: 85 %

Procedure:
500 ml of hexane and 70 ml of butyllithium (as a 2.5 molar solution in hexane) were introduced into a 1000 ml flask. 0.175 mol of 2-methylindene was added dropwise to this at ambient temperature; the mixture was stirred for a further 10 hours. 0.18 mol of trimethylsilyl chloride was then added dropwise at room temperature; the mixture was stirred for a further 10 hours. LiCl was filtered off and 70 ml of butyllithium (as a 2.5 molar solution in hexane) were added to the clear filtrate. After further stirring for 10 hours, 0.18 mol of trimethylsilyl chloride was again added and the mixture was stirred for a further 10 hours. LiCl was filtered off and the solvent was removed in vacuo. Compound 54 remained as a colorless oil. Yield: 85% of the theoretical yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[C:15](=S)[NH:14][C:13]=2[CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>C(OCCO)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[C:15]([NH:25][CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[N:14][C:13]=2[CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C1Nc2cc(OCc3ccccc3)ccc2Nc2ccccc21
Reactant: NCc1cccnc1
Solvent: CCOCCO
Product: c1ccc(COc2ccc3c(c2)N=C(NCc2cccnc2)c2ccccc2N3)cc1
Yield: 47.7 %

Procedure:
A solution of 0.6 g (1.8 mmol) of 8-benzyloxy-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-thione in 10 mL 2-ethoxyethanol was treated with 0.4 mL (3.6 mmol) of 3-(aminomethyl)pyridine and heated at reflux overnight. The solvent was removed under reduced pressure and the residue taken up in EtOAc and washed three times with H2O, then with saturated NaHCO3 solution and saturated NaCl solution. Drying over MgSO4 and removal of the solvent under reduced pressure gave the crude product. After trituration with CHCl3 /hexane, recrystallization from MeOH gave 349 mg (47.8% yield) of the product as a yellow solid, mp 196-197° C. The structure was confirmed by NMR and mass spectroscopy. (m+H)+ =407.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]#[C:15][C:16]2[CH:35]=[CH:34][C:19]3[N:20]=[C:21]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[N:33])[CH:27]=4)[CH2:22][C:23](=[O:25])[NH:24][C:18]=3[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:25]=[C:23]1[CH2:22][C:21]([C:26]2[CH:27]=[C:28]([CH:29]=[CH:30][CH:31]=2)[C:32]#[N:33])=[N:20][C:19]2[CH:34]=[CH:35][C:16]([C:15]#[C:14][C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)=[CH:17][C:18]=2[NH:24]1
Reactant: CC(C)(C)OC(=O)N1CC=C(C#Cc2ccc3c(c2)NC(=O)CC(c2cccc(C#N)c2)=N3)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(C2=Nc3ccc(C#CC4=CCNCC4)cc3NC(=O)C2)c1
Yield: 104.8 %

Procedure:
Prepared from 4-[2-(3-cyano-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-7-ylethynyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert.-butyl ester (Example 139) (573 mg, 1.13 mmol) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as an off-white solid (434 mg).
Reaction SMILES: C([SiH](CC)CC)C.Cl[C:9]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1>CC#N>[F:22][C:19]([F:20])([F:21])[C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][CH:18]=1
Reactant: FC(F)(F)c1cc(Cl)nc2ccccc12
Agent: CC[SiH](CC)CC
Solvent: CC#N
Product: FC(F)(F)c1ccnc2ccccc12
Temperature: 70 °C
Yield: 46.1 %

Procedure:
Pd (PPh3)2Cl2 (170 mg, 0.24 mmol) and triethylsilane (5.4 ml, 33.9 mmol) were added to a solution of 2-chloro-4-trifluoromethyl-quinoline 466 (5.60 g, 24.2 mmol) in MeCN (3 ml) and the mixture was heated at 70° C. for 18 h. The solvent was removed in vacuo. The crude residue was purified by column chromatography with n-hexane/EtOAc (95:5) to give the title compound (2.2 g, 47%).
Reaction SMILES: [CH3:1][C@H:2]1[C@@:41]2([OH:43])[O:42][C@H:5]([CH2:6][C@H:7]([O:64][CH3:65])[C:8]([CH3:63])=[CH:9][CH:10]=[CH:11][CH:12]=[CH:13][C@@H:14]([CH3:62])[CH2:15][C@@H:16]([CH3:61])[C:17]([C@H:19]([O:59][CH3:60])[C@H:20]([OH:58])[C:21]([CH3:57])=[CH:22][C@@H:23]([CH3:56])[C:24]([CH2:26][C@@H:27]([C@@H:44]([CH2:46][C@H:47]3[CH2:52][C@@H:51]([O:53][CH3:54])[C@H:50]([OH:55])[CH2:49][CH2:48]3)[CH3:45])[O:28][C:29]([C@H:31]3[N:36]([C:37]([C:39]2=[O:40])=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])=[O:25])=[O:18])[CH2:4][CH2:3]1.[CH3:66][C:67]1([C:79](O)=[O:80])[CH2:72][O:71]C2(CCCCCC2)[O:69][CH2:68]1.S(=O)(=O)(O)O.CCCCCC>C1COCC1.[Cl-].[Na+].O>[CH3:1][C@H:2]1[C@@:41]2([OH:43])[O:42][C@H:5]([CH2:6][C@H:7]([O:64][CH3:65])[C:8]([CH3:63])=[CH:9][CH:10]=[CH:11][CH:12]=[CH:13][C@@H:14]([CH3:62])[CH2:15][C@@H:16]([CH3:61])[C:17]([C@H:19]([O:59][CH3:60])[C@H:20]([OH:58])[C:21]([CH3:57])=[CH:22][C@@H:23]([CH3:56])[C:24]([CH2:26][C@@H:27]([C@@H:44]([CH2:46][C@H:47]3[CH2:52][C@@H:51]([O:53][CH3:54])[C@H:50]([O:55][C:68]([C:67]([CH2:79][OH:80])([CH2:72][OH:71])[CH3:66])=[O:69])[CH2:49][CH2:48]3)[CH3:45])[O:28][C:29]([C@H:31]3[N:36]([C:37]([C:39]2=[O:40])=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])=[O:25])=[O:18])[CH2:4][CH2:3]1
Reactant: CC1(C(=O)O)COC2(CCCCCC2)OC1
Reactant: CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](O)[C@H](OC)C2)CC(=O)[C@H](C)C=C(C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)C=CC=CC=C1C
Agent: CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](O)[C@H](OC)C2)CC(=O)[C@H](C)/C=C(\C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)/C=C/C=C/C=C/1C
Agent: CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C2)CC(=O)[C@H](C)/C=C(\C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)/C=C/C=C/C=C/1C
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C2)CC(=O)[C@H](C)C=C(C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)C=CC=CC=C1C
Temperature: 2.5 °C
Reaction time: 20 h

Procedure:
(160 mg) of 42-ester of rapamycin with 3-methyl-1,5-dioxaspiro[5.6]dodecane-3-carboxylic acid [IId6] was dissolved in 4 ml THF and was cooled it at 0-5° C. Subsequently, 0.5 ml 2N sulphuric acid was added and the reaction mass was stirred at 30-35° C. for 20 hrs. After completion of the reaction brine solution was added and extracted by ethyl acetate. Organic layer was separated and wash it with sodium bicarbonate solution and then by water. Dried by adding sodium sulfate and concentrate it on rotavapour to get colorless viscous oily product. Subsequently, n-hexane was added and stirred for 30 minute. White solid was precipitated, which was filtered, washed with n-hexane to get white solid product.
Reaction SMILES: [F:1][CH:2](P(=O)(C1C=CC=CC=1)C1C=CC=CC=1)[F:3].C(NC(C)C)(C)C.[Li].[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[O:32][C:33]1[CH:50]=[CH:49][C:48]2[C@@H:47]3[C@H:38]([C@H:39]4[C@@:43]([CH2:45][CH2:46]3)([CH3:44])[C:42](=O)[CH2:41][CH2:40]4)[CH2:37][CH2:36][C:35]=2[CH:34]=1.O>O1CCCC1>[F:1][C:2]([F:3])=[C:42]1[CH2:41][CH2:40][C@H:39]2[C@H:38]3[C@H:47]([CH2:46][CH2:45][C@:43]12[CH3:44])[C:48]1[CH:49]=[CH:50][C:33]([O:32][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][O:26]2)=[CH:34][C:35]=1[CH2:36][CH2:37]3
Reactant: C[C@]12CC[C@@H]3c4ccc(OC5CCCCO5)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: O=P(c1ccccc1)(c1ccccc1)C(F)F
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[C@]12CC[C@@H]3c4ccc(OC5CCCCO5)cc4CC[C@H]3[C@@H]1CCC2=C(F)F
Reaction time: 1 h
Yield: 111.9 %

Procedure:
757 mg of difluoromethyl-diphenyl-phosphine-oxide (M. L. Edwards et al. Tetrahedron Letters p. 5571, 1990) in 38 ml of tetrahydrofuran is slowly mixed with 1.5 ml of a 2 M lithium diisopropylamine solution at -50° C., stirred for 1 hour, and mixed with a solution of 1.06 g of 3-tetrahydropyranyloxy-estra-1,3,5 (10)-trien-17-one in 11 ml of tetrahydrofuran. It is stirred for 15 minutes at -50° C., allowed to come to room temperature and stirred for 3.5 hours at a bath temperature of 80° C. For working-up, it is added to water, extracted three times with ethyl acetate, the organic phases are washed neutral with saturated sodium chloride solution, dried on sodium sulfate and evaporated to dryness in a vacuum. 1.3 g of crude 17-difluoromethylene-3-(tetrahydro-pyran-2-yl-oxy)-estra-1,3,5(10)-triene is obtained.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[Br:12]Br.O>C(Cl)Cl.CC(O)=O>[Br:12][C:7]1[CH:8]=[C:2]([F:1])[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]=1[NH2:6]
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Reactant: BrBr
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(Br)cc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 140 %

Procedure:
To a mixture of 4-fluoro-2-nitroaniline (10.0 g, 42.55 mmol) in DCM (150 mL) and HOAc (75 mL) at 0° C. was added dropwise Br2 (9.9 ml, 130 mmol) at a rate to maintain the internal reaction temperature below 10° C. The reaction mixture was stirred at RT overnight and then poured into water (500 mL), followed by separation of the organic phase. The pH of the aqueous phase was adjusted to about 7 by adding NH4OH, and the mixture was extracted with DCM (100 mL×3). The combined extracts were dried (MgSO4), filtered, and concentrated in vacuo to afford 2-bromo-4-fluoro-6-nitroaniline as a yellow solid (14 g, 93%). MS (ESI): m/z=233 [M−1]−.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[N:28]1([C:34]2[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(N(CC)CC)C.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:3]1[N:4]([C:37]2[CH:36]=[CH:35][C:34]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)=[CH:39][CH:38]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2]
Reactant: CCCc1nc(CC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OB(O)c1ccc(N2CCOCC2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1nc(CC)n(-c2ccc(N3CCOCC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h
Yield: 73.1 %

Procedure:
To a suspension of 4′-[(2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.5 g), (4-morpholin-4-ylphenyl)boronic acid (0.58 g), triethylamine (0.97 mL), pyridine (0.57 mL) and molecular sieves 4 A (1 g) in dichloromethane (10 mL) was added copper(II) acetate (0.51 g) and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.53 g, 73%).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:22])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[CH2:33](I)[CH:34]=[CH2:35].[Cl-].[Na+]>C(OCC)(=O)C.C(OCC)(=O)C.CCCCCC.O1CCCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:22])[CH:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:35][CH:34]=[CH2:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCI
Reactant: O=C(Cc1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=CCC(C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
Alternately, combine (S)-4-benzyl-3-phenylacetyl-2-oxazolidinone (8.0 g, 27 mmol) and tetrahydrofuran (50 mL). cool in a dry-ice/acetone bath. Add dropwise a solution of sodium hexamethyldisilazide (30 mL, 1.0 M in tetrahydrofuran, 30 mmol). After 30 minutes, add allyl iodide (9.1 g, 54 mmol) and then replace the bath with a dry-ice/carbon tetrachloride bath. After 1.5 hours, quench the reaction by the addition of a saturated aqueous sodium chloride solution, extract with diethyl ether, and separate the layers. Extract the aqueous layer three times with diethyl ether. Combine the organic layers, extract with an aqueous 1 M hydrochloric acid solution, a saturated aqueous sodium bicarbonate solution, dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Dissolve in ethyl acetate, extract with a saturated aqueous sodium thiosulfate solution, dry the over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 10% ethyl acetate/hexane. Combine the product containing fractions, evaporate, and recrytallize from chloroform/hexane to give (S)-4-benzyl-3-(2-phenylpent-4-enoyl)-2-oxazolidinone.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:14][N:15]([CH3:17])[CH3:16])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[CH2:18]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[CH2:18]([C:28]1[CH:29]=[CH:30][C:31]([S:34]([NH:1][C@@H:2]([CH2:14][N:15]([CH3:16])[CH3:17])[CH2:3][C:4]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])(=[O:36])=[O:35])=[CH:32][CH:33]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: CCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Product: CCCCCCCCCCc1ccc(S(=O)(=O)N[C@H](CC(=O)OCc2ccccc2)CN(C)C)cc1
Yield: 94 %

Procedure:
According to the method described in example S72a, (R)-benzyl 3-amino-4-(dimethylamino)butanoate (27 mg, 0.086 mmol) was reacted with 4-decylbenzene-1-sulfonyl chloride to yield the title compound as a white solid (50 mg, 94%). MS ESI 517.4 [M+H]+, calcd for [C29H44N2O4S+H]+ 517.3
Reaction SMILES: [CH3:1][Si:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=2)[CH:9]=[CH:8]1.CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.[CH:40]([C:42]1[C:50]([O:51][CH3:52])=[CH:49][C:48]([CH3:53])=[C:47]2[C:43]=1[CH:44]=[CH:45][N:46]2[C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])=[O:41]>C1COCC1.[Li+].CC([N-]C(C)C)C>[C:57]([O:56][C:54]([N:46]1[C:47]2[C:43](=[C:42]([CH:40]([C:8]3[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:19])([CH3:18])[CH3:1])[C:15]4[C:10]([CH:9]=3)=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=4)[OH:41])[C:50]([O:51][CH3:52])=[CH:49][C:48]=2[CH3:53])[CH:44]=[CH:45]1)=[O:55])([CH3:60])([CH3:58])[CH3:59]
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C=O
Reactant: C[Si](C)(C)CCOCn1ccc2ccc(C#N)cc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Product: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(O)c1cc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-6-carbonitrile (424 mg, 1.55 mmol) in THF (0.7 mL), 1.8 M LDA in heptane/THF/ethylbenzene (139 mg, 1.29 mmol) was added at −78° C. The reaction was stirred at −78° C. for 30 minutes. tert-Butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 19-D) (250 mg, 0.86 mmol) in THF (0.7 mL) was added at −78° C. The reaction was quenched with MeOH and then a saturated aq. ammonium chloride solution. The mixture was then diluted with EtOAc and the organic layer was removed, dried over MgSO4, filtered and concentrated. The resulting residue was purified via flash chromatography (0-40% EtOAc:heptanes) to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) d ppm 8.06 (s, 1H) 7.61 (d, J=8.34 Hz, 1H) 7.51 (d, J=3.79 Hz, 1H) 7.34 (dd, J=8.21, 1.39 Hz, 1H) 6.91 (s, 1H) 6.79 (d, J=3.79 Hz, 1H) 6.63-6.71 (m, 1H) 6.20 (s, 1H) 6.09 (d, J=4.80 Hz, 1H) 5.57-5.74 (m, 2H) 3.81 (s, 3H) 3.40 (ddd, J=9.22, 6.82, 2.15 Hz, 2H) 2.55 (s, 3H) 1.50-1.63 (m, 9H) 0.78 (td, J=9.28, 6.95 Hz, 2H) −0.13-−0.09 (m, 9H).