Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5]CC)=O.[Mg].[C:13](Cl)(=O)[CH2:14]C.S(=O)(=O)(O)O>C(O)C.C(OCC)C.C(Cl)(Cl)(Cl)Cl>[C:3]([CH2:2][C:1]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:13][CH3:14]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCC(=O)Cl
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)CC(=O)CC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.5 %

Procedure:
A solution of diethyl malonate (80 g.) in ethanol (40 ml.) was added dropwise over 20 minutes to a mixture of magnesium (12.5 g.), carbontetrachloride (0.5 ml.) and ethanol (12.5 ml.) and stirred at room temperature for 10 minutes. Diethyl ether was added dropwise to the solution and refluxed under heating for 30 minutes. To the solution was added dropwise a solution of propionyl chloride (49 g.) in diethyl ether (50 ml.) under cooling over 10 minutes, and the mixture was refluxed under heating for 30 minutes. 20% sulfuric acid (200 ml.) was added to the solution, and the diethyl ether layer was separated, washed with 10% sulfuric acid and water successively, dried over magnesium sulfate and then filtered. The filtrate was evaporated in vacuo. To the oily residue was added β-naphthalene sulfonic acid hydrate (8 g.) and the mixture was heated at 200° C. for 1 hr. After cooling, diethyl ether (100 ml.) was added to the mixture and washed with 10% aqueous sodium carbonate (100 ml.) three times. The aqueous layer was extracted with diethyl ether (100 ml.) five times, and the extract was washed with water, dried over magesium sulfate and then distilled under reduced pressure (24 mmHg). The distillate at 100° to 110° C. was collected and distilled again under reduced pressure (25 mmHg). The distillate at 97° to 99° C. was collected to give ethyl propionylacetate (19.8 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[C:14]3[CH:17]=[CH:18][CH:19]=[N:20][C:13]=3[N:12]=[C:11]2[C@H:21]([N:23]([CH2:38][CH2:39][C:40](=O)[CH3:41])[C:24](=[O:37])[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([C:33]([F:36])([F:35])[F:34])[CH:27]=2)[CH3:22])=[CH:6][CH:5]=1)[CH3:2].[CH:43]1([NH2:47])[CH2:46][CH2:45][CH2:44]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.ClCCl>[CH:43]1([NH:47][CH:40]([CH3:41])[CH2:39][CH2:38][N:23]([C@@H:21]([C:11]2[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=3)[C:15](=[O:16])[C:14]3[CH:17]=[CH:18][CH:19]=[N:20][C:13]=3[N:12]=2)[CH3:22])[C:24](=[O:37])[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([C:33]([F:35])([F:36])[F:34])[CH:27]=2)[CH2:46][CH2:45][CH2:44]1
Reactant: NC1CCC1
Reactant: CCOc1ccc(-n2c([C@@H](C)N(CCC(C)=O)C(=O)Cc3ccc(F)c(C(F)(F)F)c3)nc3ncccc3c2=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CCOc1ccc(-n2c([C@@H](C)N(CCC(C)NC3CCC3)C(=O)Cc3ccc(F)c(C(F)(F)F)c3)nc3ncccc3c2=O)cc1

Procedure:
E3 (67 mg, 0.11 mmol), cyclobutyl amine (14.7 μL, 0.17 mmol), and sodium triacetoxyborohydride (73 mg, 0.34 mmol) were stirred in dichloroethane at room temperature for 3 h. The reaction mixture was diluted with dichloromethane, then washed with saturated aqueous sodium bicarbonate and brine. It was dried over magnesium sulfate, filtered, concentrated in vacuo. Purified by chromatography (4% to 10% methanol with 0.1% ammonium hydroxide in dichloromethane), recovering 31 mg of E4.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].C([O-])(=O)C.[Pb+4:17].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[CH:21][C:20]=1[Pb+3:17]
Reactant: [Pb+4]
Reactant: OB(O)c1cc(-c2ccc(Cl)cc2)ccc1Br
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Clc1ccc(-c2ccc(Br)c([Pb+3])c2)cc1
Temperature: 40 °C
Yield: 64.7 %

Procedure:
To a mixture of lead tetraacetate (3.76 g, 8.49 mmol) and mercuric diacetate (0.27 g, 0.85 mmol), thoroughly flushed with nitrogen, is added anhydrous chloroform (25 ml). This mixture is warmed to 40° C., and 4-bromo-4′-chlorobiphenyl-3-yl-boronic acid (2.40 g, 7.72 mmol) is added in one portion, and the mixture is stirred and heated at this temperature for 4 hours. After cooling to room temperature, the mixture is diluted with chloroform (25 ml), cooled in an ice-bath, and powdered anhydrous potassium carbonate (2.75 g) is added rapidly, followed by rapid stirring for 5 minutes. The solids are removed by filtration, and the filtrate is concentrated to approximately a quarter of its volume. Hexane is added to induce crystallisation, and the solvents evaporated in vacuo. Trituration with hexane gives 4-bromo-4′-chlorobiphenyl-3-yllead triacetate (3.25 g), used without further purification in the next step.
Reaction SMILES: CC(C)=O.O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].OCCCCCCCCCC[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37]>C(Cl)(Cl)Cl>[CH2:35]([C:36]([OH:38])=[O:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C(O)CCCCCCCCCCCO
Reactant: O=C(O)CCCCCCCCCCCCCCCO
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: O=C(O)CCCCCCCCCCCCCCCCC(=O)O
Reaction time: 15 h

Procedure:
In Example 3, acetone solution of 12-hydroxydodecanoic acid was replaced by 16-hydroxy hexadecanoic acid (100 mg) dissolved in chloroform (10 ml) and reaction time was set for 15 hours. 72 mg of 1,16-hexadecane dicarboxylic acid was produced.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].Cl[C:12]1[N:13]=[CH:14][C:15]2[N:20]=[C:19]([C:21]3[CH:26]=[C:25]([CH3:27])[C:24]([OH:28])=[C:23]([CH3:29])[CH:22]=3)[O:18][C:16]=2[N:17]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C(=O)C>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:12]1[N:13]=[CH:14][C:15]2[N:20]=[C:19]([C:21]3[CH:22]=[C:23]([CH3:29])[C:24]([OH:28])=[C:25]([CH3:27])[CH:26]=3)[O:18][C:16]=2[N:17]=1
Reactant: Cc1cc(-c2nc3cnc(Cl)nc3o2)cc(C)c1O
Reactant: Oc1ccccc1F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nc3cnc(Oc4ccccc4F)nc3o2)cc(C)c1O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Under argon, 0.48 g of sodium hydride (60% in mineral oil) is added a little at a time to a solution of 1.12 ml of 2-fluorophenol in 40 ml of dry N,N-dimethylacetamide. After 30 min at room temperature, a suspension of 2.78 g of 4-(5-chlorooxazolo[5,4-d]pyrimidin-2-yl)-2,6-dimethylphenol (see Ex. 1 (c)) in 60 ml of dry N,N-dimethylacetamide is added, and the reaction is stirred at 60° C. for 1.5 h and at 80° C. for 5.5 h. Another 1.12 ml of 2-fluorophenol in 40 ml of dry N,N-dimethylacetamide were then reacted under argon with 0.48 g of sodium hydride (60% in mineral oil), and this mixture was added to the reaction at room temperature. After a further 9 h at 80° C., the reaction was cooled to room temperature and neutralized with 10% strength aqueous citric acid solution. The precipitated solid was filtered off with suction, washed with water and dried under reduced pressure at 45° C. This gave 3.37 g (96%) of the title compound, which was reacted without any further purification.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2([C:20]#[N:21])[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH2:18][CH3:19])(=[O:16])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1>N.CO.[Ni]>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2([CH2:20][NH2:21])[CH2:9][CH2:10][N:11]([S:14]([CH2:17][CH2:18][CH3:19])(=[O:16])=[O:15])[CH2:12][CH2:13]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCCS(=O)(=O)N1CCC(C#N)(c2cccc(C)n2)CC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CCCS(=O)(=O)N1CCC(CN)(c2cccc(C)n2)CC1

Procedure:
A 4-(6-methylpyridin-2-yl)-1-(propylsulfonyl)piperidine-4-carbonitrile (II-4A) (2.77 g, 9 mmole) and Raney-Ni (1.5 g) in ammonia-MeOH (2M, 80 mL) was hydrogenated under H2 (55 psi) at rt o/n. After this time LCMS indicated that the reaction was completion. The catalyst was filtered and washed with MeOH (6×60 mL). The MeOH solution was concentrated on a rotary evaporator to afford {[4-(6-methylpyridin-2-yl)-1-(propylsulfonyl)piperidin-4-yl]methyl}amine (II-5) as a liquid. Anal LCMS: single peak (214 nm), 1.931 min. This product was used in next step reaction without further purification.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:62])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:61])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:60])[NH:31][C@H:32]([C@H:40]([OH:59])[CH2:41][N:42]4[C@H:51]([C:52](=[O:58])[NH:53][C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:50][C@H:49]5[C@H:44]([CH2:45][CH2:46][CH2:47][CH2:48]5)[CH2:43]4)[CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:64])[CH3:63])(=O)C.C1COCC1.[OH-].[Na+]>CO>[C:54]([NH:53][C:52]([C@@H:51]1[CH2:50][C@H:49]2[C@H:44]([CH2:45][CH2:46][CH2:47][CH2:48]2)[CH2:43][N:42]1[CH2:41][C@@H:40]([OH:59])[C@@H:32]([NH:31][C:30]([C@:14]12[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]1[C@@H:16]1[C@@:11]([CH3:61])([CH2:12][CH2:13]2)[C@@:10]2([CH3:62])[C@@H:19]([C@:20]3([CH3:23])[C@@H:7]([CH2:8][CH2:9]2)[C:6]([CH3:63])([CH3:64])[C@@H:5]([OH:4])[CH2:22][CH2:21]3)[CH2:18][CH2:17]1)=[O:60])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:58])([CH3:55])([CH3:56])[CH3:57]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H](Cc3ccccc3)[C@H](O)CN3C[C@H]4CCCC[C@H]4C[C@H]3C(=O)NC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H](Cc3ccccc3)[C@H](O)CN3C[C@H]4CCCC[C@H]4C[C@H]3C(=O)NC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.4 %

Procedure:
(1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,3R)-4-((3S,4aS,8aS)-3-(tert-butylcarbamoyl)octahydroisoquinolin-2(1H)-yl)-3-hydroxy-1-phenylbutan-2-ylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate (Example 29, 0.5 g) in MeOH:THF (8:8 ml) and cooled the contents to 0° C. then sodium hydroxide (0.12 g in 4 ml water) was added and the contents were stirred for about 6 hours at room temperature, and the completion of the reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure, the residue was taken in water and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (0.34 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.57-0.97 (m, 19H); 1.18-1.21 (m, 8H); 1.25-1.41 (m, 12H); 1.49-1.62 (m, 8H); 1.65-1.82 (m, 10H); 1.85-1.98 (m, 4H); 2.56-2.69 (m, 2H); 2.88-3.06 (m, 3H); 3.29-3.38 (m, 1H); 3.89-3.90 (m, 1H); 4.25-4.70 (m, 4H); 5.78 (s, 1H); 6.12-6.15 (d, J=9 Hz, 1H); 7.19-7.29 (m, 6H); ES Mass: 839 (100%), [M+1] 840.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:10][CH2:9][N:8]([C:11]([C:13]2([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:15][CH2:14]2)=[O:12])[CH2:7]1.O1CCCC1.O.[OH-].[Li+].O.Cl>>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2([C:11]([N:8]3[CH2:9][CH2:10][C:6]([O:5][CH2:4][C:3]([OH:29])=[O:2])([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:7]3)=[O:12])[CH2:15][CH2:14]2)=[CH:21][CH:20]=1
Reactant: COC(=O)COC1(c2ccccc2)CCN(C(=O)C2(c3ccc(Cl)cc3)CC2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COC1(c2ccccc2)CCN(C(=O)C2(c3ccc(Cl)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl[(1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-3-phenylpyrrolidin-3-yl)oxy]acetate (40.0 mg, 0.0000966 mol, example 387) in tetrahydrofuran (1 mL, 0.01 mol) was added lithium hydroxide hydrate (4.87 mg, 0.000116 mol) in water (0.5 mL, 0.03 mol). The solution was stirred at rt for 2 hours and then acidified with 1N HCl (aq.). The product was purified by prep-HPLC. LCMS: m/z 400.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH2:24][C:25]3[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=3)[C:28]([O:30]C)=[O:29])[CH3:23])=[C:18]([CH3:35])[CH:17]=2)=[C:12]([CH:36]([CH3:38])[CH3:37])[O:11][N:10]=1.[OH-].[Li+]>O1CCCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH2:24][C:25]3[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=3)[C:28]([OH:30])=[O:29])[CH3:23])=[C:18]([CH3:35])[CH:17]=2)=[C:12]([CH:36]([CH3:38])[CH3:37])[O:11][N:10]=1
Reactant: COC(=O)c1cccc(CN(C)c2ccc(OCc3c(-c4c(Cl)cccc4Cl)noc3C(C)C)cc2C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(OCc2c(-c3c(Cl)cccc3Cl)noc2C(C)C)ccc1N(C)Cc1cccc(C(=O)O)c1

Procedure:
A solution of methyl 3-{[(4-{[3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl]methoxy}-2-methylphenyl)(methyl)amino]methyl}benzoate (0.42 g, 0.76 mmol) in tetrahydrofuran (4 mL) was stirred vigorously with aqueous lithium hydroxide (2.3 ml, 0.4 M) at ambient temperature for 24 hours. The reaction was concentrated and the aqueous residue was partitioned with ethyl acetate and aqueous sodium hydrogensulfate. The organic layer was washed with brine (50 mL) and was dried over anhydrous magnesium sulfate, filtered, and condensed to a residue which was chromatographed on silica gel eluting with 10% methanol/dichloromethane. Yield=0.12 g. (30%) of 3-{[(4-{[3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl]methoxy}-2-methylphenyl)(methyl)amino]methyl}benzoic acid. 1H NMR (CDCl3, 400 MHz) δ 8.02 (s, 1H), 7.91 (d, 1H), 7.55 (d, 1H), 7.38 (m 3H), 7.31 (m, 1H), 6.95 (d, 1H), 6.33 (m, 1H), 6.57 (dd, 1H), 4.67 (s, 2H), 3.97 (s, 2H), 3.91 (s, 3H), 3.31 (m, 1H), 2.49 (s, 3H), 2.33 (s, 3H), 1.40 (d, 6H); MS (ESP+) m/e 539 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([O:26]CC)=O)[C:6]1=[O:29].[CH:32]1([NH2:35])[CH2:34][CH2:33]1>>[CH:32]1([NH:35][C:24]([C:7]2[C:6](=[O:29])[N:5]([CH2:4][C:3]([N:2]([CH3:1])[CH3:31])=[O:30])[C:14]3[C:9]([C:8]=2[OH:23])=[N:10][CH:11]=[C:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:13]=3)=[O:26])[CH2:34][CH2:33]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Product: CN(C)C(=O)Cn1c(=O)c(C(=O)NC2CC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and cyclopropylamine employing methods similar to those described in Example 9. The product was obtained as a white solid: 1H NMR (CDCl3) δ 9.96 (1H, br), 8.54 (1H, d, J=1.4 Hz), 7.13 (2H, m), 7.04-7.00 (3H, m), 4.92 (2H, s), 4.10 (2H, s), 3.11 (3H, s), 2.96 (3H, s), 2.93 (1H, m), 0.86 (2H, m, J=13, 7), 0.66 (2H, m); HRMS calcd for C23H23FN4O4+H+: 439.1781. Found: 439.1774.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH2:10][CH2:11][OH:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>C1COCC1>[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:12][CH2:11][CH2:10][C@@H:9]([C:13]([OH:15])=[O:14])[NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)O
Reactant: BrCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccc(Br)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
To a flask containing Boc-L-homoserine (5.181 g, 23.63 mmol)) in THF (50 ml) was added sodium hydride (2.93 g, 73.3 mmol) and left stirring at 0° C. for 30 minutes. The reaction mixture was warmed to RT and left for 2 hrs. 4-bromo-benzylbromide (11.81 g, 47.3 mmol) was then added as a THF solution (15 ml) dropwise. The reaction was left at RT for 20 hrs. The reaction was quenched with MeOH and the solvent removed in vacuo. The residue was dissolved in water and washed with Et2O. The aqueous layer was acidified with 2M HCl and exhaustively extracted with EtOAc. The organic layer was washed with water and brine, dried over magnesium sulphate and concentrated in vacuo. The oily residue (11 g) was purified by column chromatography eluting with 50-100% EtOAc in hexanes and flushed with 10-50% MeOH in EtOAc. Yield=927 mg, 2.388 mmol, 10% yield as a viscous oil. m/z 386/388 [M−H]+.
Reaction SMILES: C([Mg]Br)C.[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:6]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][C:25]#[N:26]>O1CCCC1>[C:25]([CH2:24][CH2:23][CH2:22][CH2:21][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]=1[C:7]1[CH:6]=[N:5][CH:10]=[CH:9][CH:8]=1)#[N:26]
Reactant: N#CCCCCBr
Reactant: c1cncc(-c2cc3ccccc3[nH]2)c1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: N#CCCCCc1c(-c2cccnc2)[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 6.0 ml of a 2M solution of ethylmagnesium bromide in tetrahydrofuran under nitrogen at 0° is added dropwise over 20 minutes a solution of 2-(3-pyridyl)indole (1.9 g) in 12 ml of tetrahydrofuran. The mixture is stirred at 0° for 0.5 hour and is then treated with a solution of 1.78 g of 5-bromovaleronitrile in 4 ml of tetrahydrofuran. This mixture is stirred at 0° for 1 hour, then at room temperature for 1 hour, and is then poured into 125 ml of ice-water. This is extracted with 2×50 ml of ether, the extract is washed with water, dried, evaporated to dryness and purified to give 3-(4-cyanobutyl)-2-(3-pyridyl)indole.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[CH:9]=2)[N:4]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:3]=1.[CH3:40][C:41]1[C:45](B2OC(C)(C)C(C)(C)O2)=[C:44]([CH3:55])[N:43]([CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([N+:63]([O-:65])=[O:64])[CH:58]=2)[N:42]=1.C(=O)([O-])[O-].[Na+].[Na+]>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].C1(C)C=CC=CC=1.C(O)C.O>[CH3:40][C:41]1[C:45]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)=[CH:13][CH:12]=4)[CH:9]=3)[N:4]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:3]=2)=[C:44]([CH3:55])[N:43]([CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([N+:63]([O-:65])=[O:64])[CH:58]=2)[N:42]=1
Reactant: Cc1nn(Cc2cccc([N+](=O)[O-])c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc([N+](=O)[O-])c4)c3C)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Yield: 43.8 %

Procedure:
Using similar reaction conditions as described in step-ii of intermediate 1, tert-butyl 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (intermediate 41) (400 mg, 0.6 mmol) was coupled with 3,5-dimethyl-1-(3-nitrobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 56) (240 mg, 0.66 mmol) in sodium carbonate (196 mg, 1 mmol), PdCl2(dppf) (22 mg, 0.03 mmol), toluene/ethanol/water (2/2/2 ml) to give 200 mg (43% yield) of titled compound after purification by column (SiO2) using 30% ethyl acetate in hexane as eluent. MS: m/z=762.3 (M+1).
Reaction SMILES: [O:1]1[C@H:3]2[C@:4]3([CH2:19][CH2:18][C@H:17]4[C@@H:8]([CH2:9][CH2:10][C:11]5[CH:12]=[C:13]([O:20][CH3:21])[CH:14]=[CH:15][C:16]=54)[C@@H:6]3[CH2:7][C@@H:2]12)[CH3:5].[N-:22]=[N+:23]=[N-:24].[Na+].CS(C)=O.C(O)(=O)C>O>[N:22]([C@H:2]1[CH2:7][C@H:6]2[C@H:8]3[C@H:17]([CH2:18][CH2:19][C@:4]2([CH3:5])[C@@H:3]1[OH:1])[C:16]1[CH:15]=[CH:14][C:13]([O:20][CH3:21])=[CH:12][C:11]=1[CH2:10][CH2:9]3)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]3O[C@@H]3C[C@@H]12
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@H](O)[C@@H](N=[N+]=[N-])C[C@@H]12
Yield: 73 %

Procedure:
5.0 g of 16α,17α-epoxy-3-methoxy-estra-1,3,5(10)-triene, 20 g sodium azide, 100 ml abs. DMSO and 30 ml glacial acetic acid are stirred at 110° C. 7 h under argon atmosphere. The mixture is then poured into water, extracted with ether, washed with 1N NaOH and then with water. After drying and removal of the solvent by distillation, the residue is chromatographed with benzene on 50 g aluminum oxide (neutral, activity level 1). Recrystallization from methanol/water yields 4.2 g (73%) of the azide.
Reaction SMILES: [C:1]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([O:25][CH:26]3CCCCO3)[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[CH:12][CH:11]=2)=[C:6]([CH2:34][CH2:35][CH3:36])[C:5]=1[OH:37])(=[O:3])[CH3:2].OCC1C=CC(C(OC)C2C=C(C=CC=2)C#N)=CC=1>>[C:1]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH:16]([O:25][CH3:26])[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[CH:14][CH:15]=2)=[C:6]([CH2:34][CH2:35][CH3:36])[C:5]=1[OH:37])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2ccc(C(OC3CCCCO3)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Agent: COC(c1ccc(CO)cc1)c1cccc(C#N)c1
Product: CCCc1c(OCc2ccc(C(OC)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O

Procedure:
The title compound is prepared in a similar manner to 3-[[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile employing 3-[(4-Hydroxymethyl-phenyl)-methoxy-methyl]-benzonitrile to afford 248 mg, 78%, as a colorless oil. LCMS M+1 430.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][C:24]1[C:25]([Cl:30])=[N:26][CH:27]=[CH:28][CH:29]=1)=[N+]=[N-].[OH-].[Na+].Cl>C1COCC1.[NH4+].[OH-].CCOCC>[NH2:20][CH2:23][C:24]1[C:25]([Cl:30])=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: [N-]=[N+]=NCc1cccnc1Cl
Agent: Cl
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: NCc1cccnc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.6 %

Procedure:
Triphenylphosphine (2.5 g, 9.5 mmol) was added to a solution of the above 3-azidomethyl-2-chloro-pyridine (1.4 g, 8.5 mmol) in anhydrous THF (30 mL) at 0° C. The reaction mixture was warmed to room temperature and stirred for 18 h. The reaction mixture was diluted with NH4OH (3 mL) and stirred for another 3 h. The mixture was then treated with 3M NaOH and stirred for 1 h. The mixture was acidified to pH 2 by adding 4M HCl solution. The mixture was diluted with ether and the layers were separated. The aqueous layer was extracted with ether and then basified with 2M NaOH solution. The aqueous solution was extracted with CH2Cl2 (×3). The combined organic phase was dried over MgSO4 and concentrated in vacuo to afford a pale yellow oily solid. This product was diluted with ether and filtered. The filtrated was concentrated to afford a pale yellow oil. The crude product was purified by silica gel column chromatography using 20:1 CH2Cl2:MeOH as an eluent to afford 0.88 g (73%) of 3-aminomethyl-2-chloropyridine as a colorless oil.