Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:16])[CH2:5][N:4]([CH2:6][C:7]2[N:11]([CH3:12])[N:10]=[C:9]([N+:13]([O-])=O)[CH:8]=2)[CH2:3]1>C(O)C>[F:16][C:2]1([F:1])[CH2:5][N:4]([CH2:6][C:7]2[N:11]([CH3:12])[N:10]=[C:9]([NH2:13])[CH:8]=2)[CH2:3]1
Reactant: Cn1nc([N+](=O)[O-])cc1CN1CC(F)(F)C1
Solvent: CCO
Product: Cn1nc(N)cc1CN1CC(F)(F)C1
Reaction time: 2 h
Yield: 100 %

Procedure:
A Parr reactor bottle was purged with nitrogen and charged with 10% palladium on carbon (30% wet, 150 mg dry weight) and a solution of 156e (1.78 mmol) in ethanol (25 mL). The bottle was attached to a Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 40 psi and shaken for 2 h. After this time, the hydrogen was evacuated, and the reaction mixture was filtered through a pad of Celite 521. The filter cake was washed with ethanol (2×25 mL), and the combined filtrates were concentrated to dryness under reduced pressure to afford a quantitative yield of 156f (360 mg) as yellow oil: MS (ESI+) m/z 203.1 (M+H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].C(N(CC)CC)C.[CH2:15]([O:22][C:23](ON1C(=O)CCC1=O)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O.CC#N>[O:7]=[C:3]1[CH:2]([NH:1][C:23](=[O:24])[O:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:6][CH2:5][NH:4]1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: NC1CCNC1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: O=C(NC1CCNC1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 69.6 %

Procedure:
To a solution of 3-aminopyrrolidin-2-one (2.70 g, 27 mmol) in water (36 mL) at ambient temperature was added triethylamine (4.12 mL, 29.7 mmol, 1.1 equivalent) followed by the dropwise addition over 15 minutes of a solution of N-(benzyloxycarbonyloxy)succinimide (7.4 g, 29.7 mmol, 1.1 equivalent) in MeCN (20 mL). The mixture was stirred at room temperature for 22 hours. The mixture was evaporated and the residue was partitioned between 0.5 M aqueous NaOH (500 mL) and DCM (600 mL). The aqueous fraction was further extracted with DCM (2×250 mL) and the combined organic extracts were back-washed with water (300 mL), dried (MgSO4) and evaporated to a cream solid which was filtered, dried and evaporated then triturated with ether (50 mL) for 0.5 hours, before being dried at room temperature for 2 hours to give benzyl N-(2-oxopyrrolidin-3-yl)carbamate (D39) 4.4 g (70%);
Reaction SMILES: [C:1]([S:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=O)[CH3:2].C[O-].[Na+].[NH2:16][C:17]1[S:21][N:20]=[C:19]([C:22](=[N:53][O:54][CH2:55][CH:56]=[CH2:57])[C:23]([NH:25][CH:26]2[C:51](=[O:52])[N:28]3[C:29]([C:35]([O:37][CH:38]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[O:36])=C(CCl)[CH2:31][S:32][C@H:27]23)=[O:24])[N:18]=1.Cl.[Cl-].[Na+]>O1CCCC1.CO.C(OCC)(=O)C>[NH2:16][C:17]1[S:21][N:20]=[C:19]([C:22](=[N:53][O:54][CH2:55][CH:56]=[CH2:57])[C:23]([NH:25][CH:26]2[C:51](=[O:52])[N:28]3[C:29]([C:35]([O:37][CH:38]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)=[O:36])=[C:2]([CH2:1][S:4]/[CH:5]=[CH:6]\[C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH2:31][S:32][C@H:27]23)=[O:24])[N:18]=1
Reactant: CC(=O)S/C=C\c1ccccc1
Reactant: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1nsc(N)n1
Agent: C[O-]
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CS/C=C\c3ccccc3)CS[C@H]12)c1nsc(N)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46.7 %

Procedure:
To a solution of (Z)-2-acetylthiovinylbenzene (500 mg) in tetrahydrofuran (5 ml) was dropwise added a solution of sodium methoxide (13.9 mg) in a mixture of methanol (358 mg) and tetrahydrofuran (2 ml) under ice-cooling. The mixture was stirred for 30 minutes under the same condition. The resulting solution was dropwise added to a solution of benzhydryl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylate (syn isomer) (1.46 g) in tetrahydrofuran (20 ml) at -30° C. The mixture was stirred at the same temperature for 30 minutes. The reaction temperature was gradually raised to 0° C. 1N Hydrochloric acid (3 ml) was added to the reaction mixture at 0° C. Ethyl acetate and a saturated aqueous solution of sodium chloride were added to the mixture. The separated organic layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated in diisopropyl ether to give a solid, which was subjected to column chromatography on silica gel (50 g) and eluted with a mixture of chloroform and methanol (100:1, V/V). The fractions containing the object compound were combined and concentrated in vacuo. The residue was triturated in diisopropyl ether to give benzhydryl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-[(Z)-2-phenylvinylthiomethyl]-3-cephem-4-carboxylate (syn isomer) (790 mg).
Reaction SMILES: O[CH:2]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.[ClH:22]>>[ClH:22].[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)=[CH:19][CH:18]=1
Reactant: COc1ccc(C(O)CCCCCCn2ccnc2)cc1
Agent: Cl
Product: COc1ccc(C=CCCCCCn2ccnc2)cc1

Procedure:
Treat the compound prepared in Example 53 with 1.1 eq. of 0.1N HCl to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1>C1CCCCC1>[CH:2]1([O:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cc1ccc(CCO)cc1
Solvent: C1CCCCC1
Product: Cc1ccc(CCOC2CCCCC2)cc1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
246 grams of cyclohexane is added to a stirred slurry of p-methyl phenyl beta ethanol (408 grams) and 25 grams of Amberlyst® 15 cation exchange resin maintained at 110° C., over a 2 hour period. The reaction mass is then aged at 110° C. for an additional 3 hours whereupon it is cooled and filtered. The resulting solution is then heated at reflux with 80 grams of 30% aqueous sodium hydroxide. The reaction mass is then cooled and the resulting organic layer is washed with 1 liter of water. The organic layer is separated from the reaction mass and distilled through a 11/2"×12" Goodlow packed column to afford the following distillation fractions:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:4]=1[CH:5]=O.C([CH2:18][S:19]([CH2:22][S:23]([CH2:26][C:27](O)=O)(=[O:25])=[O:24])(=[O:21])=[O:20])(O)=O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:4]=1/[CH:5]=[CH:18]/[S:19]([CH2:22][S:23](/[CH:26]=[CH:27]/[C:4]1[C:7]([O:13][CH3:14])=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:3]=1[O:2][CH3:1])(=[O:24])=[O:25])(=[O:20])=[O:21]
Reactant: COc1cc(OC)c(C=O)c(OC)c1
Reactant: O=C(O)CS(=O)(=O)CS(=O)(=O)CC(=O)O
Solvent: CC(=O)O
Product: COc1cc(OC)c(/C=C/S(=O)(=O)CS(=O)(=O)/C=C/c2c(OC)cc(OC)cc2OC)c(OC)c1
Yield: 68 %

Procedure:
A solution of 2,4,6-trimethoxybenzaldehyde (2 mmol) and carboxymethane-sulfonylmethanesulfonyl-acetic acid (1 mmol) in acetic acid (10 mL) was subjected to General Procedure 1, to yield the title compound in 68% yield. m.p. 140-142° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:9]1[CH:10]=[N+:11]([O-:16])[CH:12]=[C:13](Br)[CH:14]=1.[C-:17]#[N:18].[Na+]>CN(C=O)C.O>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:9]1[CH:10]=[N+:11]([O-:16])[CH:12]=[C:13]([C:17]#[N:18])[CH:14]=1
Reactant: CN1CCC[C@H]1COc1cc(Br)c[n+]([O-])c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCC[C@H]1COc1cc(C#N)c[n+]([O-])c1

Procedure:
A sample of 3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5bromo-pyridine-N-oxide, from Example 98a above, is reacted with sodium cyanide in DMF and water according to standard procedures. The solvents are removed, and the product is extracted, then purified by chromatography on silica gel.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[N:21]1([C:27]2[N:32]=[CH:31][C:30]([CH:33]=O)=[CH:29][CH:28]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:33]([C:30]3[CH:31]=[N:32][C:27]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:28][CH:29]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1ccc(N2CCOCC2)nc1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4ccc(N5CCOCC5)nc4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 74.1 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50 mg, 0.148 mmol) and 6-Morpholin-4-yl-pyridine-3-carbaldehyde (31.2 mg, 0.163 mmol) were reacted to produce 56 mg (74%) of the title compound. mp: 288-290° C., 1H NMR (300 MHz, DMSO-d6): 13.14 (s, 1H), 8.87 (s, 1H), 8.21 (d, J=8 Hz, 2H), 7.98 (s, 1H), 7.74 (s, 1H), 7.20 (s, 1H), 7.02 (m, 2H), 6.36 (s, 2H), 5.25 (t, J=8 Hz, 1H), 3.72 (br s, 4H), 3.57 (br s, 4H), 3.29 (s, 1H), 2.88 (s, 1H), 2.75 (s, 1H), 2.61 (d, J=7 Hz, 1H), 2.25 (d, J=8 Hz, 1H), 1.38 (d, J=8 Hz, 1H). MS: 510, 512 (M+H), HPLC: 1.96 min (G method).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].Br[CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27].BrCC1CCCCO1>>[CH3:27][CH:26]([CH3:28])[CH2:25][CH2:24][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: CC(C)CCBr
Agent: BrCC1CCCCO1
Product: CC(C)CCN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and 1-bromo-3-methylbutane to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1′-(3-methylbutyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (64%) as a colorless solid: mp 134-137° C. (hexanes); 1H NMR (300 MHz, CDCl3) δ7.30 (ddd, J=7.7, 7.7, 1.3 Hz, 1H), 7.15 (dd, J=7.2, 0.9 Hz, 1H), 7.03 (ddd, J=7.4, 7.4, 0.7 Hz, 1H), 6.89 (d, J=7.8 Hz, 1H), 6.49 (s, 1H), 6.20 (s, 1H), 4.88 (d, J=9.0 Hz, 1H), 4.62 (d, J=9.0 Hz, 1H), 4.21-4.16 (m, 2H), 4.14-4.09 (m, 2H), 3.89-3.80 (m, 1H), 3.73-3.63 (m, 1H), 1.75-1.59 (m, 3H), 1.00 (d, J=6.3 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ177.3, 155.4, 144.6, 142.5, 138.3, 132.8, 128.9, 124.0, 123.2, 121.3, 111.6, 108.6, 99.4, 80.2, 64.6, 64.0, 58.1, 38.9, 36.3, 26.2, 22.7, 22.6; MS (ES+) m/z 366.3 (M+1); Anal. Calcd for C22H23NO4: C, 72.31; H, 6.34; N, 3.83. Found: C, 72.21; H, 6.31; N, 3.55.
Reaction SMILES: Cl.C(OC1C=CC(C(N)=N)=CC=1)C.C(OC(=O)C(=COCC)C#N)C.CC[O-].[Na+].[OH-].[Na+].[C:32]([C:34]1[C:35](O)=[N:36][C:37]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH3:48])=[CH:42][CH:41]=2)=[N:38][CH:39]=1)#[N:33].P(Cl)(Cl)([Cl:52])=O>C(O)C>[Cl:52][C:35]1[C:34]([C:32]#[N:33])=[CH:39][N:38]=[C:37]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH3:48])=[CH:42][CH:41]=2)[N:36]=1
Reactant: CCOc1ccc(-c2ncc(C#N)c(O)n2)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: CCOC=C(C#N)C(=O)OCC
Agent: CCOc1ccc(C(=N)N)cc1
Agent: CC[O-]
Solvent: CCO
Product: CCOc1ccc(-c2ncc(C#N)c(Cl)n2)cc1

Procedure:
The starting material can be obtained according to the procedure of A. R. Todd and F. Bergel, J. Chem. Soc. 1937, 365 by reaction of p-ethoxybenzamidine hydrochloride with α-ethoxymethylene-α-cyanoacetic acid ethyl ester and sodium ethylate in ethanol and then with sodium hydroxide solution. The resulting 5-cyano-4-hydroxy-2-(4-ethoxyphenyl)-pyrimidine (melting point 288.6°-290.5° C) is treated with phosphorus oxychloride to give 4-chloro-5-cyano-2-(4-ethoxyphenyl)-pyrimidine having a melting point of 190.6°-192.4° C.
Reaction SMILES: [F:1][CH:2]([F:12])[CH:3]1[CH2:6][CH:5]([C:7]([O:9]CC)=[O:8])[CH2:4]1.[OH-].[Na+]>C1COCC1.O>[F:1][CH:2]([F:12])[CH:3]1[CH2:6][CH:5]([C:7]([OH:9])=[O:8])[CH2:4]1
Reactant: CCOC(=O)C1CC(C(F)F)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CC(C(F)F)C1
Reaction time: 16 h
Yield: 71.2 %

Procedure:
To a stirred solution of Intermediate 252A (0.2 g, 1.122 mmol) in THF (5 mL) was added NaOH (0.112 g, 2.81 mmol) in water (2 mL) at RT. After 16 h, THF was removed under a reduced pressure and the pH of aqueous solution was adjusted to 3 using a 1.0 N aq. solution of HCl and extracted with ethyl acetate (3×10 mL). The combined organic layer was washed with water, brine, dried over Na2SO4, filtered and the filtrate concentrated to afford Intermediate 252B as yellow liquid (0.12 g, 71%, mixture of cis and trans isomers). The crude product was used in a subsequent reaction without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.01-12.22 (m, 1H), 5.84-6.32 (m, 1H), 2.97-3.13 (m, 1H), 2.59-2.77 (m, 1H), 2.06-2.32 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[N:16][O:17][CH3:18])[C:13](O)=[O:14].CN(C)C=O.S(Cl)([Cl:31])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[N:16][O:17][CH3:18])[C:13]([Cl:31])=[O:14]
Reactant: O=S(Cl)Cl
Reactant: CON=C(C(=O)O)c1ccccc1COc1cc(C)ccc1C
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CON=C(C(=O)Cl)c1ccccc1COc1cc(C)ccc1C
Temperature: 60 °C
Reaction time: 5 h

Procedure:
2-[2-(2,5-Dimethylphenoxymethyl)phenyl]-2-methoxyiminoacetic acid (9.40 g, 30 mmol, E/Z=20/80) was dissolved in dimethylformamide (DMF)(0.11 g, 1.5 mmol) and toluene (20 ml). A solution of 95% thionyl chloride (4.13 g, 33 mmol) and toluene (10 ml) was added dropwise at 60° C. over 5 hours. The mixture was stirred at 60° C. for 5 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to a total amount of 30 g to give crude 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyiminoacetyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1.[CH3:22][N:23]([CH3:32])[CH2:24][CH2:25][CH2:26][C:27](=O)[C:28]([OH:30])=[O:29]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:27]([C:28]([OH:30])=[O:29])[CH2:26][CH2:25][CH2:24][N:23]([CH3:32])[CH3:22])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1
Reactant: CN(C)CCCC(=O)C(=O)O
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1
Product: CN(C)CCCC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1)C(=O)O

Procedure:
In the manner given in Example 13, 7-chloro-2-hydrazino-5-(o-chlorophenyl)-3H-1,4-benzodiazepine can be stirred with 5-(dimethylamino)-2-oxopentanoic acid at room temperature to give 7-chloro-2-[[1-carboxy-4-(dimethylamino)butylidene]hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: [C@@H:1]12[CH2:7][NH:6][C@@H:5]1[CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2]2.[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][C:22](I)=[CH:21][N:20]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:25][C:24]1[CH:23]=[C:22]([N:6]2[CH2:7][C@@H:1]3[C@H:5]2[CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:2]3)[CH:21]=[N:20][C:19]=1[Cl:18]
Reactant: O=C(OCc1ccccc1)N1C[C@@H]2CN[C@@H]2C1
Reactant: Clc1cc(I)cnc1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: O=C(OCc1ccccc1)N1C[C@@H]2CN(c3cnc(Cl)c(Cl)c3)[C@@H]2C1
Yield: 25 %

Procedure:
The product of Example 52D (451 mg, 1.94 mmol) was coupled with 2,3-dichloro-5-iodopyridine (805 mg, 2.94 mmol; U.S. Pat. No. 7,733,912) using tris(dibenzylideneacetone)dipalladium (Pd2(dba)3, 36 mg, 0.039 mmol; Alfa Aesar), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP, 82 mg, 0.13 mmol; Strem), and sodium tert-butoxide (360 mg, 3.75 mmol; Aldrich) according to the procedure described in Example 1E to provide the title compound (184 mg, 25% yield). MS (DCI/NH3) m/z 378, 380 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:19]([O:20][CH2:21][O:22][CH3:23])=[CH:18][C:17]2[CH2:16][CH2:15][CH:14]3[CH:6]([CH2:7][CH2:8][C:9]4([CH3:25])[CH:13]3[CH2:12][CH2:11][C:10]4=[O:24])[C:5]=2[CH:4]=1)[CH3:2].CO.[BH4-].[Na+]>C1COCC1>[CH2:1]([C:3]1[C:19]([O:20][CH2:21][O:22][CH3:23])=[CH:18][C:17]2[CH2:16][CH2:15][CH:14]3[CH:6]([CH2:7][CH2:8][C:9]4([CH3:25])[CH:13]3[CH2:12][CH2:11][CH:10]4[OH:24])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(cc1OCOC)CCC1C2CCC2(C)C(=O)CCC12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cc2c(cc1OCOC)CCC1C2CCC2(C)C(O)CCC12
Yield: 86.6 %

Procedure:
To a stirred, rt, solution of 2-Et-3-O-MOM estrone 52 (743 mg, 2.18 mmol) in THF (10 mL)/methanol (40 mL) solution was added sodium borohydride (76 mg, 2 mmol). After one hour the reaction was quenched by addition of ammonium chloride (2 mL of saturated solution), diluted with ethyl acetate (50 mL) and water (25 mL), the organic layer separated and washed with water, brine, dried and evaporated. Column chromatography (hexane/ethyl acetate gradient) gave the desired alcohol 53 as a clear colourless oil (650 mg) which showed δH (400 MHz, CDCl3, ref. TMS=0) 7.09 (1H, s, ArH), 6.78 (1H, s, ArH), 5.17 (2H, s, OCH2), 3.69-3.78 (1H, m, CHOH) 3.48 (3H, s, OMe), 2.78-2.86 (2H, m, 6-CH2), 2.61 (2H, q, J 7.4, CH2Me), 1.24-2.38 (13H, m), 1.19 (3H, t, J 7.4, CH2Me) and 0.77 (3H, s, 18-CH3).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[O:16][C:15]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])=[N:14][C:13]=2[CH2:23][CH2:24][CH2:25][C:26](OCC)=[O:27])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[O:16][C:15]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])=[N:14][C:13]=2[CH2:23][CH2:24][CH2:25][CH2:26][OH:27])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCc1nc(-n2ccnc2C)oc1-c1ccc(F)c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nccn1-c1nc(CCCCO)c(-c2ccc(F)c3ccccc23)o1
Reaction time: 1 h

Procedure:
Ethyl 5-(4-fluoro-1-naphthyl)-2-(2-methyl-1-imidazolyl)-4-oxazolebutanoate (401 mg) was dissolved in 10 ml of tetrahydrofuran, to which was added gradually lithium aluminum hydride (50 mg) under ice-cooling, and the mixture was stirred for 1 hour. Water (0.1 ml) was carefully added to the reaction mixture, which was filtered. The residue on the filter paper was washed with ethyl acetate. The filtrate was concentrated to give crystals of 5-(4-fluoro-1-naphthyl)-2-(2-methyl-1-imidazolyl)-4-oxazolebutanol. Recrystallization from acetone-diethyl ether gave colorless prisms (294 mg, 82%). Melting point 107-109° C.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([CH3:26])[CH:20]=[CH:19][C:18]([S:21]([NH:24][NH2:25])(=[O:23])=[O:22])=[CH:17][CH:16]=1>C(O)C>[C:15]1([CH3:26])[CH:16]=[CH:17][C:18]([S:21]([NH:24][N:25]=[C:1]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:22])=[O:23])=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: O=C(c1ccccc1)c1ccccc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)NN=C(c2ccccc2)c2ccccc2)cc1

Procedure:
Benzophenone (15.0 parts, 0.082M ex Fluka) was stirred at reflux with p-toluene sulphonylhydrazine (15.33 parts, 0.082M ex Aldrich) in ethanol (125 ml) for 10 hours. Gradually a pale yellow solution formed from which the hydrazone gradually precipitated. After cooling to 20° C., diethylether (20 ml) was added and the hydrazone filtered and washed with ether. The hydrazone was obtained as a white powder (24.0 parts; 83% theory) mp 184°-6° C.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:13][CH2:14][CH:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[OH:16].[BH4-].[Na+]>CO.O.CCOC(C)=O>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:13][CH2:14][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[OH:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: NCC(O)c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)c1ccc(CNCC(O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1 ml of 4-tert-butylbenzaldehyde (6.15 mmol) and 960 mg of [rac]-2-amino-1-(4-chloro -phenyl)-ethanol (estimated 4.1 mmol) were dissolved in 40 ml methanol at rt, and after stirring for 5 min at rt, were refluxed for 2 h. After cooling down to rt, 310 mg (8.2 mmol) of sodium borohydride were added and after stirring for 15 min at rt, the reaction mixture was then refluxed for 2 h. After cooling down to rt, the residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was stirred with a small quantity of diethylether/heptane, filtered and the solid dried under high vacuo, leading to 723 g of [rac]-(4-tert-butyl-benzyl)-[2-(4-chloro-phenyl)-2-hydroxy-ethyl]-amine as a white solid (55%). MS (ISP) 318.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][CH:25]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]2)=[N:22][CH:23]=1.[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([F:53])[C:39]=1[OH:54]>>[Cl:37][C:38]1[CH:43]=[C:42]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C:18]2[CH:23]=[N:22][C:21]([NH:24][CH:25]3[CH2:29][CH2:28][NH:27][CH2:26]3)=[CH:20][CH:19]=2)[CH:41]=[C:40]([F:53])[C:39]=1[OH:54]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: O=C(c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1ccc(NC2CCNC2)nc1)C1CC1
Yield: 45 %

Procedure:
Following general procedure D, tert-butyl 3-(5-(6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino)pyridin-2-ylamino)pyrrolidine-1-carboxylate (100 mg, 0.18 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (73 mg, 0.27 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (42 mg, 45% over 2 steps) as a yellow solid: NMR (500 MHz, MeOD+TFA-d) δ 9.40 (br s, 1H), 8.22 (dd, J=8.8, 2.0 Hz, 1H), 8.17-8.06 (m, 2H), 8.00 (d, J=8.8 Hz, 1H), 7.55 (dd, J=8.9, 2.7 Hz, 1H), 7.19-7.13 (m, 2H), 6.83-6.76 (m, 1H), 4.65-4.56 (m, 1H), 3.66-3.49 (m, 2H), 3.45-3.30 (m, 2H), 2.87 (br s, 1H), 2.48-2.37 (m, 1H), 2.19-2.08 (m, 1H), 1.28-1.16 (m, 4H). ESI MS m/z 518 [C28H25ClFN5O2+H]+; HPLC>99.0% (AUC), tR=10.43 min.