Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][C:14]=3[F:25])=[O:9])=[CH:4][CH:3]=1.C(Cl)Cl>[Pd].C([O-])([O-])=O.[Ca+2].CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16](/[CH:21]=[CH:22]\[CH2:23][OH:24])=[CH:15][C:14]=3[F:25])=[O:9])=[CH:26][CH:27]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(C#CCO)cc2c1O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: CO
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(/C=C\CO)cc2c1O
Reaction time: 2 h

Procedure:
To a solution of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Example No. 53 (0.24 g) in 60 mL 3:1 CH2Cl2 :MeOH was added a spatula tip of 5% Pd/CaCO3. The reaction was placed under hydrogen balloon atmosphere. After 2 hours, the Pd catalyst was filtered over Celite, new catalyst added to the filtrate and the reaction again placed under a hydrogen balloon. This regeneration of catalyst was repeated 8 times and the reaction monitored by MS until complete. The reaction mixture was filtered over celite and the filter cake washed thoroughly with MeOH and CH2Cl2. The filtrate was concentrated under reduced pressure to give a tan solid which was a 2:1 mixture of desired product and over-reduced material as shown by NMR. This mixture was further purified by HPLC (Cyclobond 2000) to give the desired product (0.072 g, 30%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[B:9]1[O:17][C:14]([CH3:16])([CH3:15])[C:11]([CH3:13])([CH3:12])[O:10]1)=O.[C:18]([NH:26][NH2:27])(=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>C([O-])(=O)C.[Na+]>[CH3:12][C:11]1([CH3:13])[C:14]([CH3:16])([CH3:15])[O:17][B:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH:1]=[N:27][NH:26][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[O:10]1
Reactant: NNC(=O)c1ccncc1
Reactant: CC1(C)OB(c2ccccc2C=O)OC1(C)C
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CC1(C)OB(c2ccccc2C=NNC(=O)c2ccncc2)OC1(C)C
Temperature: 100 °C
Reaction time: 0.07 h
Yield: 67 %

Procedure:
A portion of (2-formylphenyl)boronic acid pinacol ester (1 mmol, 0.232 g) was added to a nearly saturated solution of isonicotinic acid hydrazide (1 mmol, 0.137 g) in 0.1 M pH 4.5 sodium acetate buffer. The reaction mixture was stirred over an oil bath at 100° C. in for 4 min. The white insoluble product was collected via vacuum filtration, washed with water, and dried in vacuo to give an off-white powder in 67% yield. Recrystallization by slow evaporation of CH2Cl2 or vapor diffusion of CH2Cl2 and hexanes afforded translucent plates suitable for X-ray diffraction. 1H NMR (DMSO): δ 1.341 (12H, s), 7.447 (2H, td, J=1.20, J=6.47), 7.565 (1H, t, J=7.07), 7.736 (1H, d, J=6.72), 7.818 (2H, dd, J=1.47, J=4.49), 8.029 (1H, d, J=7.68), 8.791 (2H, d, J=5.8), 8.963 (1H, s), 12.20 (1H, s); 13C NMR (DMSO): δ 62.07, 121.45, 138.27, 159.21, 163.11, 166.70, 168.59, 173.04, 176.79, 186.85, 187.74, 187.89; MS (ESI): m/z 352.3 (M+H+), 374.3 (M+Na+), 350.1 (M−H+); IR (neat, cm−1): 3179, 3059, 2974, 1643, 1550, 1479, 1346, 1292, 1141. 1056; UV-vis (MeOH) nm (M−1 cm−1): 208 (20,320), 302 (19,530).
Reaction SMILES: [Na].[CH3:2][Si](C)(C)N[Si](C)(C)C.[C:11]([O:15][C:16]([N:18]1[C@@H:22]([CH2:23][C:24]2([CH:27]=O)[CH2:26][CH2:25]2)[CH2:21][O:20][C:19]1([CH3:30])[CH3:29])=[O:17])([CH3:14])([CH3:13])[CH3:12]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[C:11]([O:15][C:16]([N:18]1[C@@H:22]([CH2:23][C:24]2([CH:27]=[CH2:2])[CH2:25][CH2:26]2)[CH2:21][O:20][C:19]1([CH3:30])[CH3:29])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC2(C=O)CC2)COC1(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na]
Solvent: C1CCOC1
Product: C=CC1(C[C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
27.05 g of sodium-hexamethyldisilazane are added in portions to a suspension of 52.7 g of methyltriphenylphosphonium bromide in 470 ml of tetrahydrofuran in the course of 10 min. 20.9 g of 3-tert-butoxycarbonyl-2,2-dimethyl-4(S)-[(1-formylcyclopropyl)methyl]-1,3-oxazolidine are added dropwise to this mixture at 5° C. in the course of 10 min, and after warming to room temperature, the mixture is stirred for 1 h. The mixture is poured onto ice-water and the aqueous phase is extracted with methylene chloride. The title compound is purified by means of FC over 900 g of silica gel (mobile phase G): Rf (G)=0.56.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[CH2:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1O)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C1[O:22]C1.[H][H]>[Ru]>[CH2:2]1[O:3][CH2:1]1.[CH2:4]([C:13]1([OH:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: [H][H]
Reactant: CCCCCCCCCc1ccccc1O
Agent: [Ru]
Solvent: C1CO1
Product: CCCCCCCCCC1(O)CCCCC1
Temperature: 100 °C

Procedure:
To 70 ml autoclave, 20 g (45.4 mmoles) of nonylphenol ethylene-oxide adduct having an ethylene oxide addition mole number of 5.0 and 2.0 g of powdery 5%-ruthenium alumina were charged. The reaction system was substituted with nitrogen, successively with hydrogen, and heated to 100° C. Hydrogen pressure was respectively controlled to the pressure shown in Table 2. Hydrogenation reaction was carried out for the time and at the temperature shown in Table 2 while feeding hydrogen so as to maintain the hydrogen pressure constant. After the reaction, the catalyst was filtered at 90° C. under increased pressure to obtain nonylcyclohexanol ethylene oxide adduct having an ethylene oxide addition mole number of 5.0. Table 2 shows amounts of consumed hydrogen, residual nonylphenol ethylene oxide adduct and nonylcyclohexane.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:13]([C:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)(=[O:17])[CH2:14][CH2:15][CH3:16].CCN=C=NCCCN(C)C>ClCCl.CN(C1C=CN=CC=1)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([N:21]3[CH2:22][CH2:23][C:18]([C:13](=[O:17])[CH2:14][CH2:15][CH3:16])([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:19][CH2:20]3)=[O:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: CCCC(=O)C1(c2ccccc2)CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCC(=O)C1(c2ccccc2)CCN(C(=O)c2ccc3[nH]ccc3c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Indole-5-carboxylic acid (177 mg, 1.1 mmole) and 4-butyryl-4-phenylpiperidine (231 mg, 1.0 mmole) were dissolved in 10 ml dichloromethane. To this solution was added catalytic DMAP and EDCI (330 mg, 1.1 mmole). The resulting solution was then stirred at room temperature overnight. The reaction was worked up by washing sequentially with 1N HCl, saturated sodium bicarbonate, and saturated sodium chloride. The compound was then purified by flash chromatography on silica gel (40:1 CHCl3/MeOH). 1H NMR (300 Mhz, CDCl3) δ 8.60 (s, 1H), 7.66 (d, 1H), 7.38-7.18 (m, 8H), 6.53 (d, 1H), 4.28 (bs, 1H), 3.67 (bs, 1H), 3.39 (t, 2H), 2.42 (bs, 2H), 2.18 (m, 3H), 1.88 (bs, 1H), 1.41 (m, 2H), 0.66 (t, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH:7]([Cl:8])[CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1.[C:16](Cl)(=[O:18])[CH3:17]>C(O)C>[C:16]([NH:1][CH2:2][CH:3]1[CH:7]([Cl:8])[CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1)(=[O:18])[CH3:17]
Reactant: NCC1CN(Cc2ccccc2)CC1Cl
Reactant: CC(=O)Cl
Solvent: CCO
Product: CC(=O)NCC1CN(Cc2ccccc2)CC1Cl
Yield: 78.3 %

Procedure:
To 3-aminomethyl-1-benzyl-4-chloropyrrolidine (2.69 g) is added ethanol (50 ml) and thereto is added dropwise acetyl chloride (1.02 g) with stirring under ice-cooling. The mixture is stirred at room temperature overnight, then concentrated, neutralized with saturated aqueous sodium hydrogen carbonate, and extructed with dichloromethane. The dichloromethane layer is dried and concentrated to give 3-acetylaminomethyl-1-benzyl-4-chloropyrrolidine (2.50 g) as an yellow oil.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:35])=[C:7]([NH:9][C:10](=[O:34])[C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[N:27]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:13][CH:12]=2)[CH:8]=1.S(Cl)([Cl:38])=O>ClCCl>[Cl:38][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:35])=[C:7]([NH:9][C:10](=[O:34])[C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[N:27]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:13][CH:12]=2)[CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(CO)cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Solvent: ClCCl
Product: Cc1ccc(CCl)cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 110 %

Procedure:
To a suspension of N-(5-hydroxymethyl-2-methylphenyl)-4-(4-phenylquinazolin-2-ylamino)benzamide (1.88 g, 4.08 mmol) in dichloromethane (50 mL) that had been cooled to 0° C. in an ice bath was added slowly thionyl chloride (475 μL, 6.54 mmol), and the mixture was stirred at 0° C. for 2 h. Excess thionyl chloride and dichloromethane were removed on a rotary evaporator. The residue was stirred with ether, filtered, washed with ether, and dried to give N-(5-chloromethyl-2-methylphenyl)-4-(4-phenylquinazolin-2-ylamino)benzamide as a yellow solid (2.15 g, 100%). This material was then added to a 1.6 M solution of methylamine in tetrahydrofuran (20 mL, 32 mmol) that had been cooled to 0° C. in an ice bath. The stirred mixture was allowed to warm to rt overnight and then was concentrated on a rotary evaporator. The residue was redissolved in dichloromethane, washed with saturated sodium bicarbonate and dried over sodium sulfate. The solvent was then removed on a rotary evaporator and the residue purified by flash column chromatography to give N-{2-methyl-5-[(methylamino)methyl]-phenyl}-4-[(4-phenylquinazolin-2-yl)amino]benzamide (1.12 g, 57%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.33 (s, 1H), 9.71 (s, 1H), 8.17 (d, 2H), 8.00 (d, 2H), 7.89-7.79 (m, 5H), 7.65 (m, 3H), 7.42 (m, 1H), 7.34 (s, 1H), 7.21 (d, 1H), 7.12 (d, 1H), 3.65 (s, 2H), 2.28 (s, 3H), 2.23 (s, 3H). MS (EI) for C30H27N5O: 474.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33]2[S:37][C:36]([C:38]3([O:42]CC4C=CC(OC)=CC=4)[CH2:41][O:40][CH2:39]3)=[N:35][CH:34]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][CH2:17][N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[CH:15]=3)[N:8]([S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:5]2=[N:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([C:33]2[S:37][C:36]([C:38]3([OH:42])[CH2:41][O:40][CH2:39]3)=[N:35][CH:34]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][CH2:17][N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[CH:15]=3)[N:8]([S:23]([C:26]3[CH:27]=[CH:28][C:29]([CH3:30])=[CH:31][CH:32]=3)(=[O:25])=[O:24])[C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(COC2(c3ncc(-c4c(Cl)cnc5c4cc(-c4cnn(CCN6CCCC6)c4)n5S(=O)(=O)c4ccc(C)cc4)s3)COC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2c(-c3cnn(CCN4CCCC4)c3)cc3c(-c4cnc(C5(O)COC5)s4)c(Cl)cnc32)cc1
Reaction time: 0.5 h

Procedure:
To an ambient solution of 5-(5-chloro-2-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(3-(4-methoxybenzyloxy)oxetan-3-yl)thiazole (Example 20B) (160 mg, 0.215 mmol) in dichloromethane (2.5 mL) was added trifluoroacetic acid (2.5 mL, 32.4 mmol). The reaction was stirred for 0.5 hours and then concentrated to dryness under reduced pressure. The residue was partitioned between ethyl acetate (5 mL) and saturated aqueous bicarbonate solution (1 mL). The organic layer was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with 0 to 10% methanol in dichloromethane, to give the title compound. MS ESI(+) m/z 625.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.C[Si](C)(C)[N:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[O:19])=[O:8])=[CH:5][CH:4]=1
Reactant: C[Si](C)(C)N1CCCC1=O
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)N2CCCC2=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
24.4 g. of p-methoxybenzoyl chloride and 22.5 g. of 1-trimethylsilyl-2-pyrrolidinone are mixed and the mixture is stirred at room temperature for 10 minutes. Then, the resulting trimethylchlorosilane is distilled off under reduced pressure in an oil bath at 80° C. The residue is triturated with 100 ml. of diethyl ether. The mixture is filtered and the filter cake is recrystallized from ethanol. There is obtained 1-(p-methoxybenzoyl)-2-pyrrolidinone having a melting point of 120°-121° C.
Reaction SMILES: [C:1]([Si:5]([CH3:26])([CH3:25])[O:6][C@@H:7]([C@@H:9]1[C@@H:12]([C@H:13]([C:15](SC2C=CC=CC=2)=[S:16])[CH3:14])[NH:11][C:10]1=[O:24])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:27]([O:30][C:31]([N:33]1[CH2:37][C@@H:36]([SH:38])[CH2:35][C@H:34]1[C:39](=[O:43])[N:40]([CH3:42])[CH3:41])=[O:32])[CH:28]=[CH2:29]>C(#N)C>[CH2:27]([O:30][C:31]([N:33]1[CH2:37][C@@H:36]([S:38][C:15]([C@@H:13]([C@H:12]2[NH:11][C:10](=[O:24])[C@@H:9]2[C@H:7]([O:6][Si:5]([C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:25])[CH3:26])[CH3:8])[CH3:14])=[S:16])[CH2:35][C@H:34]1[C:39](=[O:43])[N:40]([CH3:41])[CH3:42])=[O:32])[CH:28]=[CH2:29]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=S)Sc1ccccc1
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1C(=O)N(C)C
Solvent: CC#N
Product: C=CCOC(=O)N1C[C@@H](SC(=S)[C@H](C)[C@H]2NC(=O)[C@@H]2[C@@H](C)O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)N(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.1 %

Procedure:
To a mixture of (3S,4S)-3-[(1R)-1-(tertbutyldimethylsilyloxy)ethyl]-4-[(1R)-1-{(phenylthio)thiocarbonyl}ethyl]-2-oxoazetidine (100 mg) and cuprous chloride (30 mg) in acetonitrile (1 ml) was added (2S,4S)-1-allyloxycarbonyl-2-(dimethylcarbamoyl)-4-mercaptopyrrolidine (130 mg) and the mixture was stirred at the ambient temperature for 5 hours. The mixture was purified by preparative thin layer chromatography (developed with ethyl acetate) to give (3S,4S)-4-[(1R)-1-{((2S,4S)-1-allyloxycarbonyl-2-(dimethylcarbamoyl)pyrrolidin- 4-ylthio)thiocarbonyl}ethyl]-3-[(1R)-1-(tertbutyldimethylsilyloxy)ethyl]-2-oxoazetidine (105 mg).
Reaction SMILES: CCO[C:4]([CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])=[O:5].[NH2:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:19]=2[N:20]=1>CC(C)=O>[CH3:26][O:25][C:23]1[CH:22]=[CH:21][C:19]2[N:20]=[C:16]([NH:15][C:4](=[O:5])[CH2:6][C:7](=[O:8])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[S:17][C:18]=2[CH:24]=1
Reactant: COc1ccc2nc(N)sc2c1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Solvent: CC(C)=O
Product: COc1ccc2nc(NC(=O)CC(=O)c3ccccc3)sc2c1

Procedure:
Ethyl benzoyl acetate (9.5 ml) and 2-amino-6-methoxy benzothiazole (9.01 g) are heated to 140° under house vacuum for 2 hours. After cooling, the residue is taken up in acetone and filtered. The precipitate is dissolved in hot DMF to give an amide, N-(6-methoxybenzothiazol-2-yl)-3-oxo-3-phenylpropanamide (II).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.[CH3:6][C:7](=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>P(=O)(O)(O)O>[CH2:9]([C:8]([C:7](=[O:13])[CH3:6])=[CH:2][C:1]([OH:5])=[O:4])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCCC(C)=O
Reactant: O=CC(=O)O
Agent: O=P(O)(O)O
Product: CCCCC(=CC(=O)O)C(C)=O

Procedure:
Prepared from glyoxylic acid (15.2 g, 0.17 mol), 2-heptanone (34.2 g, 0.3 mol) and orthophosphoric acid (30 ml). 1H n.m.r. δ (CDCl3) 0.91, t J 7.2 Hz, 3H, CH3; 1.38, m, 4H, CH2; 2.39, s, 3H, CH3; 2.77, t J 7.2 Hz, 2H, CH2; 6.49, s, CH.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C@H:29]1[CH2:34][C@H:33]2[C@H:35]3[C@H:44]([CH2:45][CH2:46][C@:31]2([CH3:32])[CH2:30]1)[C:43]1[CH:42]=[CH:41][C:40]([O:47][CH3:48])=[CH:39][C:38]=1[CH2:37][CH2:36]3>ClCCl>[Br:1][C@@H:29]1[CH2:34][C@H:33]2[C@H:35]3[C@H:44]([CH2:45][CH2:46][C@:31]2([CH3:32])[CH2:30]1)[C:43]1[CH:42]=[CH:41][C:40]([O:47][CH3:48])=[CH:39][C:38]=1[CH2:37][CH2:36]3
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C[C@@H](O)C[C@@H]12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C[C@H](Br)C[C@@H]12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred suspension of 2.67 g (15.0 mmol) N-bromosuccinimide in 18 ml dry dichloromethane, a solution of 3.93 g (15.0 mmol) triphenylphosphine in 18 ml dry dichloromethane is added dropwise at 10° C. After 5 min, 1.72 g (6.0 mmol) 16β-hydroxy-3-methoxy-estra-1,3,5(10)-triene are added and the mixture is stirred at room temperature for 2 h. After column chromatography of the reaction product on silica gel (60 g) using 300 ml of dichloromethane, the target compound is obtained in the form of colorless crystals.
Reaction SMILES: [CH:1]1([C@H:6]2[C:37](=[O:38])[N:36]3[CH2:39][C@@H:33]([CH2:34][C@H:35]3[C:40](=[O:56])[NH:41][C@:42]3([C:47](=[O:55])[NH:48][S:49]([CH:52]4[CH2:54][CH2:53]4)(=[O:51])=[O:50])[CH2:44][C@H:43]3[CH:45]=[CH2:46])[O:32][C:18]3=[N:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:26]([O:27][CH2:28][C:29](O)=[O:30])=[C:17]3[CH2:16][CH:15]=[CH:14][CH2:13][CH2:12][C@@H:11]3[CH2:57][CH2:58][CH2:59][C@H:10]3[O:9][C:8](=[O:60])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:61]1[CH2:65][CH2:64][CH2:63][CH2:62]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]1([C@H:6]2[C:37](=[O:38])[N:36]3[CH2:39][C@@H:33]([CH2:34][C@H:35]3[C:40]([NH:41][C@:42]3([C:47](=[O:55])[NH:48][S:49]([CH:52]4[CH2:54][CH2:53]4)(=[O:50])=[O:51])[CH2:44][C@H:43]3[CH:45]=[CH2:46])=[O:56])[O:32][C:18]3=[N:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:26]([O:27][CH2:28][C:29](=[O:30])[N:61]4[CH2:65][CH2:64][CH2:63][CH2:62]4)=[C:17]3[CH2:16][CH:15]=[CH:14][CH2:13][CH2:12][C@@H:11]3[CH2:57][CH2:58][CH2:59][C@H:10]3[O:9][C:8](=[O:60])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CCC=CCc1c(nc3ccccc3c1OCC(=O)O)O2)C(=O)NS(=O)(=O)C1CC1
Reactant: C1CCNC1
Agent: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CC/C=C/Cc1c(nc3ccccc3c1OCC(=O)N1CCCC1)O2)C(=O)NS(=O)(=O)C1CC1
Agent: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CC/C=C/Cc1c(nc3ccccc3c1OCC(=O)O)O2)C(=O)NS(=O)(=O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CCC=CCc1c(nc3ccccc3c1OCC(=O)N1CCCC1)O2)C(=O)NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of {[(3aR,7S,10S,12R,21E,24aS)-7-cyclopentyl-10-({(1R,2S)-1-[(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}carbamoyl)-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,20,23,24,24a-tetradecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinolin-19-yl]oxy}acetic acid (Example 66) (27 mg) in DMF (0.5 mL) was added pyrrolidine (5.27 μL), DIPEA (0.028 mL) and HATU (14.53 mg). The reaction mixture was stirred at room temperature for 15 minutes. The reaction was quenched with water and 5% KHSO4 until pH=3. More water was added and the mixture was stirred 5 minutes. The white solid was filtered (washed with water). This solid was dissolved in ethyl acetate and the mixture was dried over magnesium sulfate, filtered and concentrated to afford the desired product (26 mg). HRMS (ES+) m/z 901.4109 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]([CH2:12][CH3:13])[C:8]([NH:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[F:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH2:12][CH3:13])[C:8]([NH:10][CH3:11])=[O:9])=[CH:14][CH:15]=1
Reactant: CCC(Oc1ccc(O)cc1)C(=O)NC
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCC(Oc1ccc(OCc2ccccc2F)cc1)C(=O)NC

Procedure:
In analogy to the procedure described in Example 3 b), the alkylation of (RS)-2-(4-hydroxy-phenoxy)-N-methyl-butyramide with 2-fluoro-benzylbromide in 2-butanone using potassium carbonate as the base yielded the (RS)-2-[4-(2-fluoro-benzyloxy)-phenoxy]-N-methyl-butyramide as a white solid; MS: m/e=318 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]([CH3:11])=[C:5]2[CH2:12][C:13](OC)=[O:14]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]([CH3:11])=[C:5]2[CH2:12][CH2:13][OH:14]
Reactant: COC(=O)CC1=C(C)Cc2ccc(F)cc21
Solvent: C1CCOC1
Product: CC1=C(CCO)c2cc(F)ccc2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
To a solution of methyl 5-fluoro-2-methyl-3-indenyl-acetate (24 g) in dry THF (300 ml) lithiumaluminum hydride (6.9 g) is added. The mixture is stirred at room temperature for 1.5 hours. Excess LiAlH4 is destroyed with saturated aqueous NaHSO4 solution. The organic phase is concentrated in vacuo, and the crude product is purified via silica gel column chromatography elution with methylene chloride. The residue is recrystallized from hexane to give 5-fluoro-2-methyl-1H-3-indenyl-(2-hydroxy)ethane (yield 63%; m.p. 65°-66.5° C).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[CH2:7]([O:9][C:10]([C:12]1[C:13]2[CH2:21][CH2:20][CH2:19][CH2:18][C:14]=2[S:15][C:16]=1[NH2:17])=[O:11])[CH3:8].Cl>N1C=CC=CC=1>[CH2:7]([O:9][C:10]([C:12]1[C:13]2[CH2:21][CH2:20][CH2:19][CH2:18][C:14]=2[S:15][C:16]=1[NH:17][C:4]([CH:1]1[CH2:3][CH2:2]1)=[O:5])=[O:11])[CH3:8]
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1c(NC(=O)C2CC2)sc2c1CCCC2
Reaction time: 1 h

Procedure:
11 millimol cyclopropanecarbonyl chloride was added dropwise to the solution of 10 millimol IV in 25 milliliter pyridine at 5° C. The reaction mixture was stirred at this temperature for 1 hour, poured onto icecold 1N aqueous HCl, the precipitated solid was filtered off, washed with water and n-hexane, then dried.
Reaction SMILES: COC([C:5]1([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]([CH2:10][S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:18])=O.[I-].[Li+]>>[CH2:23]([O:22][C:20]([CH2:19][CH:5]1[CH:9]([CH2:10][S:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7][C:6]1=[O:18])=[O:21])[CH3:24]
Reactant: CCOC(=O)CC1(C(=O)OC)C(=O)CCC1CSc1ccccc1
Agent: [I-]
Agent: [Li+]
Product: CCOC(=O)CC1C(=O)CCC1CSc1ccccc1
Yield: 78.7 %

Procedure:
In accordance with the process of Example 25, 1-ethoxycarbonylmethyl-2-oxo-5-phenylthiomethyl-cyclopentanecarboxylic acid methyl ester (640 mg; 1.83 m mol) and lithium iodide (250 mg; 1.85 m mol) were used to obtain 420 mg of 2-ethoxycarbonylmethyl-3-phenylthiomethyl-cyclopentanone as an oil.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH:5]=[CH:4][CH:3]=[N:2]1.[N+:9]([C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([N+]([O-])=O)[C:13]=1[C:14]#[N:15])([O-:11])=[O:10]>>[N:1]1([CH2:6][CH2:7][O:8][C:16]2[CH:17]=[CH:18][CH:19]=[C:12]([N+:9]([O-:11])=[O:10])[C:13]=2[C:14]#[N:15])[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: OCCn1cccn1
Product: N#Cc1c(OCCn2cccn2)cccc1[N+](=O)[O-]
Yield: 89.2 %

Procedure:
Prepared as in Example 197197c from 2-(1H-pyrazol-1-yl)ethanol and 2,6-dinitrobenzonitrile in 89.2% yield. MS 259 (MH+).