Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:40])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:31])/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[CH:17][C:16]=1[Cl:32].[N:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[C:43]([CH:51]=O)[CH:42]=1>O1CCCC1>[CH3:9][O:10][C:11](=[O:40])/[C:12](/[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:31])/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[CH:17][C:16]=1[Cl:32])=[CH:51]/[C:43]1[CH:42]=[N:41][C:50]2[C:45]([CH:44]=1)=[CH:46][CH:47]=[CH:48][CH:49]=2
Reactant: O=Cc1cnc2ccccc2c1
Reactant: COC(=O)C(NC(=O)c1ccc(C(O)/C=C/c2cccc(O)c2)cc1Cl)P(=O)(OC)OC
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1cnc2ccccc2c1)NC(=O)c1ccc(C(O)/C=C/c2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
1,1,3,3-Tetramethylguanidine (60 μL, 0.48 mmol) was added to a solution of rac.-(E)-N-[2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)prop-2-en-1-yl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 135; 116 mg, 0.24 mmol) in tetrahydrofuran (5 mL) at −20° C. After 10 min, quinoline-3-carboxaldehyde (40 mg, 0.255 mmol) was added and the solution was stirred at room temperature for 16 h. After the solvent was removed in vacuo, the residue was taken up in ethyl acetate (10 mL) and the solution was washed with saturated sodium bicarbonate solution (10 mL) and brine (10 mL). Each aqueous layer was back-extracted with ethyl acetate (10 mL). The combined organic extracts were dried, filtered, evaporated and chromatographed (50% ethyl acetate/hexanes) to give rac.-(Z)-2-[[2-chloro-4-[(E)-1-hydroxy-3-(3-hydroxyphenyl)prop-2-en-1-yl]benzoyl]amino]-3-(quinolin-3-yl)propenoic acid methyl ester (110 mg, 89% yield) as a colorless solid.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]([N:14]1[C:18]2[N:19]=[C:20]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[NH:21][C:22](=[O:23])[C:17]=2[CH:16]=[N:15]1)[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.CS(C)=[O:42]>ClCCl>[C:3]([CH:4]([N:14]1[C:18]2[N:19]=[C:20]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[NH:21][C:22](=[O:23])[C:17]=2[CH:16]=[N:15]1)[CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:42])[CH3:2]
Reactant: COc1ccc(Cc2nc3c(cnn3C(CCO)CCCc3ccccc3)c(=O)[nH]2)cc1
Reactant: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cc2nc3c(cnn3C(CCCc3ccccc3)C(C)=O)c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
151 mg (0.35 mmol) of 1-[1-(-hydroxy-ethyl)-4-phenyl-butyl]-6-(4-methoxy-benzyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one are dissolved in 1 ml of DMSO and 3.5 ml of dichloromethane, and the solution is cooled to 0° C. 0.485 ml of triethylamine and 245 mg of SO3/pyridine complex are added, and the mixture is stirred for 15 hours at room temperature. The mixture is diluted with 20 ml of dichloromethane, extracted with 1N HCl and saturated NaHCO3 solution, the extract is dried over Na2SO4, and the solvent is removed in vacuo. Purification by chromatography (PE-EA=2:1) gives 115 mg (76%), M.p.: 129° C.
Reaction SMILES: Cl.C([N:9]1[C:13]([CH:14]([OH:25])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][N:11]=[CH:10]1)C1C=CC=CC=1.Cl.[H][H]>[Pd].C(O)C>[OH:25][CH:14]([C:13]1[N:9]=[CH:10][NH:11][CH:12]=1)[CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OC(CCCCc1ccccc1)c1cncn1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: OC(CCCCc1ccccc1)c1c[nH]cn1

Procedure:
1-benzyl-5-(1-hydroxy-5-phenylpentyl)-1H-imidazole hydrochloride (8,5 g), prepared in the Step a, is hydrogenated in the mixture of 100 ml of 2N hydrochloric acid and 10 ml of ethanol at 60° C. Pd/C (10%) as catalyst. When the uptake of the hydrogen ceases, the reaction mixture is cooled, filtered and evaporated to dryness. Water is added and the mixture is made alkaline with sodium hydroxide. The product is then extracted to methylene chloride which is washed with water, dried with sodium sulphate and evaporated to dryness. The residue is the product as base, and it is used as such in Step c.
Reaction SMILES: [N:1]1([C:10]2[N:18]=[C:17](Cl)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH2:20][CH:21]([CH2:24][OH:25])[CH2:22][OH:23]>CS(C)=O>[N:1]1([C:10]2[N:18]=[C:17]([NH:20][CH:21]([CH2:24][OH:25])[CH2:22][OH:23])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Clc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Reactant: NC(CO)CO
Solvent: CS(C)=O
Product: OCC(CO)Nc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Temperature: 120 °C
Yield: 38 %

Procedure:
200 mg of product obtained in stage 1 above are mixed with 3 ml of DMSO and 336 mg (5 equivalents) of 2-amino-1,3-propanediol, and the mixture is then heated at 120° C. for approximately 72 hours. The mixture is allowed to return to ambient temperature. Purification is carried out by chromatography on silica with a CH2Cl2-MeOH—NH4OH: 90-9-1 mixture for eluent. Evaporation is carried out and a paste is formed in methylene chloride-methanol: 50-50. Partial drying and drying under vacuum at 50° C. are carried out. 91.4 mg of expected product are obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH2:10]([N:12](CC)CC)C.CN.C1COCC1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6]([NH:12][CH3:10])(=[O:8])=[O:7]
Reactant: O=S(=O)(Cl)CCCCCl
Reactant: CCN(CC)CC
Agent: CN
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNS(=O)(=O)CCCCCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chlorobutane-1-sulfonyl chloride (117 mmol) and triethyl amine (117 mmol) in dichloro methane (250 ml) at 0° C. was added a 2M solution of methyl amine in THF (117 mmol) dropwise. The mixture was allowed to warm to room temperature with stirring overnight. The organic solution was washed with H2O and extracted with CH2Cl2, dried over MgSO4 and filtered. The solution was concentrated. The product was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]1[S:22][CH:23]([CH2:26][C:27]([OH:29])=O)[CH2:24][N:25]=1)[NH:6]2.C[N:31](C)C=O.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:13])=[O:14])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]1[S:22][CH:23]([CH2:26][C:27]([NH2:31])=[O:29])[CH2:24][N:25]=1)[NH:6]2
Reactant: CN(C)C=O
Reactant: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C3=NCC(CC(=O)O)S3)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C3=NCC(CC(N)=O)S3)cc12
Temperature: 25 °C
Yield: 92 %

Procedure:
To a mixture of (2-{4-methyl-7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (0.25 g), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (0.11 g) and N,N-dimethylformamide (15 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.14 g) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 2 days. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=9:1-10:0), and the obtained colorless oil was crystallized from ethyl acetate-hexane to give the title compound (228 mg, yield: 92%) as colorless crystals. MS:449(MH+), melting point 120-121° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[C:14]3[NH:21][CH:20]=[C:19]([C:22]([OH:24])=O)[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([NH:38][C:22]([C:19]2[C:15]3[N:16]=[CH:17][N:18]=[C:13]([C:7]4[CH:8]=[CH:9][C:10]([F:12])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:14]=3[NH:21][CH:20]=2)=[O:24])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: O=C(O)c1c[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc12
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A76) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]3[CH3:17])=[N:7][C:6]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:33])OC4C=CC=CC=4)=[CH:20][CH:19]=3)=[N:5][C:4]=2[CH2:3]1.CCN(CC)CC.[NH2:41][CH2:42][CH2:43][CH2:44][OH:45]>CN(C=O)C>[OH:45][CH2:44][CH2:43][CH2:42][NH:41][C:25]([NH:24][C:21]1[CH:20]=[CH:19][C:18]([C:6]2[N:7]=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]3[CH3:17])[C:9]3[CH2:10][N:2]([CH3:1])[CH2:3][C:4]=3[N:5]=2)=[CH:23][CH:22]=1)=[O:33]
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)nc2c1CN(C)C2
Reactant: NCCCO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NCCCO)cc2)nc2c1CN(C)C2
Temperature: 50 °C
Yield: 24.2 %

Procedure:
To a stirring solution of (S)-phenyl 4-(6-methyl-4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenylcarbamate (intermediate 10) (50 mg, 0.12 mmol) in dry DMF, was added Et3N (51 μL, 0.36 mmol) and 3-aminopropan-1-ol (42 μL, 0.56 mmol). The reaction mixture was then heated at 50° C. for 2 hours. The solvent was then removed in vacuo and the crude residue was purified by prep. LCMS (high pH) affording the title compound as clear oil (12.5 mg, 0.029 mmol, 26%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]2[C:9](=[O:10])[N:8]([CH:11]3[CH2:16][CH2:15][C:14](=[O:17])[NH:13][C:12]3=[O:18])[C:7](=[O:19])[C:6]=12.[CH3:20]I.O>CN(C=O)C>[CH3:20][NH:1][C:2]1[S:3][CH:4]=[C:5]2[C:9](=[O:10])[N:8]([CH:11]3[CH2:16][CH2:15][C:14](=[O:17])[NH:13][C:12]3=[O:18])[C:7](=[O:19])[C:6]=12
Reactant: Nc1scc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CI
Solvent: CN(C)C=O
Solvent: O
Product: CNc1scc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 80 °C

Procedure:
0.084 g of 1-amino-5-(2,6-dioxopiperidin-3-yl)-5H-thieno(3,4-c)pyrrole-4,6-dione was dissolved in 10 mL of DMF, and 0.5 mL of methyl iodide were added. The reaction mixture was heated to 80° C., allowed to react at that temperature for 6 h, cooled, and 100 mL of water were added. The reaction solution was extracted with ethyl acetate (3×30 mL). The organic phases were combined, washed with 30 mL of and 30 mL of brine, dried over anhydrous MgSO4, filtered, and evaporated to dryness. The remaining residue was purified on silica gel column chromatography to yield a solid (0.033 g). MS (m/z): 292 (M−1)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[N:16])[CH:13]=2)[NH:8][CH:7]=1.C(C1C=C2C(=CC=1)NC=C2)#N.ClCCCC(Cl)=[O:33].[Cl-].[Al+3].[Cl-].[Cl-]>>[OH:1][CH2:2][CH2:3][CH2:4][C:5]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[N:16])[CH:13]=2)[NH:8][CH:7]=1)=[O:33]
Reactant: O=C(Cl)CCCCl
Reactant: N#Cc1ccc2[nH]cc(CCCCO)c2c1
Agent: N#Cc1ccc2[nH]ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Product: N#Cc1ccc2[nH]cc(C(=O)CCCO)c2c1

Procedure:
The present inventors have further surprisingly and unexpectedly found that 3-(4-hydroxybutyl)-1H-indole-5-carbonitrile intermediate can be prepared, in high purity and with high yield, by reacting 5-cyanoindole with 4-chlorobutyryl chloride in the presence of aluminium chloride to produce an intermediate compound, followed by reacting the compound with an aqueous alcohol to produce 3-(4-hydroxybutyryl)-1H-indole-5-carbonitrile, which is then reduced with sodium cyanoborohydride in the presence of hydrochloric acid and water in acetonitrile solvent to produce 3-(4-hydroxybutyl)-1H-indole-5-carbonitrile.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[CH:11]=[C:12]([CH:14]=[C:15]([C:17]2[S:21][CH:20]=[N:19][CH:18]=2)[CH:16]=1)[NH2:13].[CH3:22][C:23]1([CH3:34])[CH:28]([CH3:29])[C:27](=[O:30])[CH2:26][CH2:25][CH:24]1[C:31]([OH:33])=[O:32]>C1COCC1.CCOC(C)=O>[NH2:13][C:12]1[CH:14]=[C:15]([C:17]2[S:21][C:20]([C:27]3([OH:30])[CH2:26][CH2:25][CH:24]([C:31]([OH:33])=[O:32])[C:23]([CH3:22])([CH3:34])[CH:28]3[CH3:29])=[N:19][CH:18]=2)[CH:16]=[C:10]([CH3:9])[CH:11]=1
Reactant: Cc1cc(N)cc(-c2cncs2)c1
Reactant: CC1C(=O)CCC(C(=O)O)C1(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(N)cc(-c2cnc(C3(O)CCC(C(=O)O)C(C)(C)C3C)s2)c1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 12.3 %

Procedure:
Lithium diisopropylamide (5110 μl, 9.20 mmol) was added to a −78° C. solution of 3-methyl-5-(1,3-thiazol-5-yl)aniline (500 mg, 2.63 mmol) in THF (7 mL). The reaction was allowed to warm to −60° C. while aging for 30 min. The solution was cooled to −78° C. and 2,2,3-trimethyl-4-oxocyclohexanecarboxylic acid (600 mg, 3.26 mmol) in THF (6 mL) was added portionwise, maintaining an internal temperature below −65° C. After 5 min at −78° C. the reaction was warmed to room temperature, diluted with EtOAc and washed with aqueous saturated ammonium chloride (3×). The combined aqueous portion was extracted with 10% IPA:CHCl3 (3×). The combined organic layers were dried under reduced pressure to yield 4-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-4-hydroxy-2,2,3-trimethylcyclohexanecarboxylic acid (121 mg, 12%) as a yellow oil. MS ESI: [M+H]+ m/z 375.
Reaction SMILES: I[CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:13][C:14]1[C:15]2[N:16]([C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:22]([CH3:24])[N:23]=2)[CH:17]=[C:18]([CH3:20])[CH:19]=1.O>CN(C=O)C>[CH3:24][C:22]1[N:23]=[C:15]2[C:14]([O:13][CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5])=[CH:19][C:18]([CH3:20])=[CH:17][N:16]2[C:21]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)c1c(C)nc2c(O)cc(C)cn12
Reactant: CC(C)CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C)nc2c(OCCC(C)C)cc(C)cn12
Temperature: 60 °C
Reaction time: 0.67 h

Procedure:
1.23 ml (9.4 mmol) of 1-iodo-3-methylbutane and 6.12 g (18.8 mmol) of caesium carbonate were added to 2.0 g (8.5 mmol) of ethyl 8-hydroxy-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate Example 239A in 122.3 ml of DMF, and the mixture was stirred at 60° C. for 40 min. 900 ml of water were added to the reaction mixture, which had cooled to RT, and the mixture was stirred at RT for 1 h, and the precipitated solid was filtered off, washed with water and dried under high vacuum. This gave 2.25 g (84% of theory; purity 97%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@H:11]2[C@H:12]3[C@H:21]([CH2:22][CH2:23][C@:9]2([CH3:10])[C@@H:8]([OH:26])[CH2:7]1)[C:20]1[CH:19]=[CH:18][C:17]([O:24][CH3:25])=[CH:16][C:15]=1[CH2:14][CH2:13]3)=[O:5])[CH3:2].[CH2:27](Cl)[O:28][CH3:29].O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C@@H:6]1[C@H:11]2[C@H:12]3[C@H:21]([CH2:22][CH2:23][C@:9]2([CH3:10])[C@@H:8]([O:26][CH2:27][O:28][CH3:29])[CH2:7]1)[C:20]1[CH:19]=[CH:18][C:17]([O:24][CH3:25])=[CH:16][C:15]=1[CH2:14][CH2:13]3)=[O:5])[CH3:2]
Reactant: COCCl
Reactant: CCOC(=O)[C@H]1C[C@H](O)[C@@]2(C)CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@H]12
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)[C@H]1C[C@H](OCOC)[C@@]2(C)CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@H]12
Yield: 86.1 %

Procedure:
A solution of 59.9 mg (0.155 mmol) of 55, 269 μL (1.55 mmol) of iPrEt2N, 118 μL (1.55 mmol) of MOMCl in anhydrous toluene (2 mL) was stirred at rt for 22 h. The reaction mixture was poured into H2O (70 mL) and extracted with CH2Cl2 (3×, 50 mL). Combined organic extracts were dried over Na2SO4 and concentrated in vacuo giving a yellow oil. Purification by flash chromatography on a 2×17 cm column of silica gel using 3:1 hexanes/EtOAc as eluent gave 53.7 mg (80%) of 56. Data for 56: TLC, T-2, Rf 0.8; 1H NMR (500 MHz, CDCl3) δ 0.85 (s, 3H, H-18), 1.29 (t, 3H, J=7.2 Hz, CH2CH3), 3.37 (s, 3H, —CH2OCH3), 3.77 (t, 1H, J=8.7 Hz, H-17α), 3.78 (s, 3H, ArOCH3), 4.20–4.14 (m, 2H, —CH2CH3), 4.66 (s, 2H, OCH2O), 6.61 (d, 1H, J=2.8 Hz, H-4), 6.71 (dd, 1H, J=8.8, 2.8 Hz, H-2), 7.21 (d, 1H, J=8.8 Hz, H-1).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:34])[CH2:18][C:19]3[CH:24]=[CH:23][C:22](B4OC(C)(C)C(C)(C)O4)=[CH:21][CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl[C:36]1[C:41]([F:42])=[CH:40][N:39]=[CH:38][N:37]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:34])[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:36]4[C:41]([F:42])=[CH:40][N:39]=[CH:38][N:37]=4)=[CH:21][CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2)CC1
Reactant: Fc1cncnc1Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(-c4ncncc4F)cc3)nc2)CC1
Temperature: 110 °C

Procedure:
A mixture of N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide 196-1 (30 mg, 0.065 mmol), 4-chloro-5-fluoropyrimidine 196-2 (28 mg, 0.21 mmol) Pd(PPh3)4 (12 mg, 0.01 mmol) and K3PO4 (90 mg, 0.424 mmol) in dioaxane (0.6 mL) was flushed with nitrogen and heated to 110° C. for 2 hours. The salt was removed by filtration and the filtrate was taken to dryness by rotary evaporation. The residue was purified by reverse phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-(5-fluoropyrimidin-4-yl)phenyl)acetamide 196. MS m/z 435.10 (M+1). 1H NMR 400 MHz (DMSO-d6) δ10.54 (s, 1H), 9.06 (d, 1H), 8.90 (d, 1H), 7.98 (m, 3H), 7.86 (d, 1H), 7.49 (d, 2H), 7.37 (m, 1H), 3.73 (s, 2H), 3.50 (m, 4H), 3.09 (t, 2H), 3.02 (t, 2H), 1.97 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][C:22]=3[CH2:27][CH:28]=[CH2:29])([CH3:20])[C@@H:18]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:38][C:39]([F:66])([C:56]([F:65])([F:64])[C:57]([F:63])([F:62])[C:58]([F:61])([F:60])[F:59])[CH2:40][CH2:41][CH:42]([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]C=C)[C:43]([O:45][CH2:46][CH3:47])=[O:44]>ClCCl.C(P(C1CCCCC1)(C1CCCCC1)C1CCCCC1)(P(C1CCCCC1)(C1CCCCC1)C1CCCCC1)C1C=CC=CC=1.Cl[Ru]Cl>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][C:22]=3[CH2:27][CH:28]=[CH:29][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH:42]([CH2:41][CH2:40][C:39]([F:38])([F:66])[C:56]([F:64])([F:65])[C:57]([F:62])([F:63])[C:58]([F:59])([F:61])[F:60])[C:43]([O:45][CH2:46][CH3:47])=[O:44])([CH3:20])[C@@H:18]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCC1=C2c3ccc(OCc4ccccc4)cc3CC[C@H]2[C@@H]2CC[C@H](OCc3ccccc3)[C@@]2(C)C1
Reactant: C=CCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Agent: Cl[Ru]Cl
Agent: c1ccc(C([PH](C2CCCCC2)(C2CCCCC2)C2CCCCC2)[PH](C2CCCCC2)(C2CCCCC2)C2CCCCC2)cc1
Solvent: ClCCl
Product: CCOC(=O)C(CCCCCCC=CCC1=C2c3ccc(OCc4ccccc4)cc3CC[C@H]2[C@@H]2CC[C@H](OCc3ccccc3)[C@@]2(C)C1)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 47.6 %

Procedure:
Benzylidenebis(tricyclohexylphosphine)-dichlororuthenium (90 mg, 0.1 mmol) was added to a solution of 3,17β-bis(benzyloxy)-11-(2-propenyl)estra-1,3,5(10),9(11)-tetraene (1.0 g, 2.0 mmol) and ethyl 2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-decenoate (1.81 g, 4.1 mmol) in dichloromethane (20 ml), followed by heating under reflux for 5 hours under nitrogen atmosphere. After cooling, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel flash chromatography (eluent: hexane/ethyl acetate=4/1) to give ethyl 11-[3,17β-bis(benzyloxy)estra-1,3,5(10),9(11)-tetraen-11-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-undecenoate (863 mg, Yield 48%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([O-])=[S:7])([O-:3])=[O:2].[NH2:13][C:14]([NH2:16])=[NH:15].C(O)C>O1CCCC1>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH:15][C:14]([NH2:16])=[NH:13])=[S:7])([O-:3])=[O:2]
Reactant: N=C(N)N
Reactant: O=[N+]([O-])c1ccccc1C([O-])=S
Solvent: C1CCOC1
Solvent: CCO
Product: N=C(N)NC(=S)c1ccccc1[N+](=O)[O-]

Procedure:
The reactions of Equation 57 above can be run by methods known in the art. Thus, in reaction 57a, a 2-nitrothiobenzoate of Formula (LXXV) is reacted with guanidine in a solvent such as ethanol or tetrahydrofuran at 0° to about 30° C. for 2 to 120 hours to form a 2-nitrothiobenzoylguanidine of Formula (LXXVI), according to the teachings of J. Goerdeler and A. Fincke, Chem. Ber., 89, 1033 (1956). In reaction 57b, LXXVI is cyclized by reaction with bromine in methanol at 0° to 60° C. for 0.5 to 3 hours to form a 3-amino-5-(2-nitrophenyl)-1,2,4-thiadiazole of Formula (LXXVII), according to the teachings of ibid. In reaction 57c, LXXVII is reacted with sodium nitrite in hydrochloric acid or hydrobromic acid, in the presence of copper powder, at -10° to 60° C. for 0.5 to 5 hours to form Xq' via Sandmeyer reaction, according to the teachings of F. Kurzer and S. Taylor, J. Chem. Soc., 3234 (1960). And in the last reaction, Xq' is reacted with sodium methoxide, sodium ethoxide or sodium methylmercaptide in a solvent such as methanol, ethanol or tetrahydrofuran at reflux for 0.5 to 5 hours to form Xq", according to the teachings of ibid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([C:28]([O:30]CC)=[O:29])=[O:27])[CH2:22][CH2:21]2)=[O:19])=[CH:12][C:11]=1[N+:33]([O-:35])=[O:34].[Li+].[OH-].O.Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([C:28]([OH:30])=[O:29])=[O:27])[CH2:22][CH2:21]2)=[O:19])=[CH:12][C:11]=1[N+:33]([O-:35])=[O:34]
Reactant: CCOC(=O)C(=O)N1CCN(C(=O)/C=C/c2ccc(Sc3ccc(Cl)cc3Cl)c([N+](=O)[O-])c2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(=O)N1CCN(C(=O)/C=C/c2ccc(Sc3ccc(Cl)cc3Cl)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
To a stirred solution of the ethyl ester (40 mg, 0.074 mmol) from Example 43A in 2 mL of ethanol was added saturated LiOH (0.25 mL). The mixture was then stirred at room temperature for 2 hours. Water (2 mL) was then added to the reaction mixture, which was then acidified to pH=2 with concentrated HCl. The precipitates were collected through filtration, washed with cold water, dried under vacuum to give the titled compound (30 mg, 79%) as light yellow solid. 1H NMR (d6 -DMSO, 300 MHz) δ 3.52 (br m, 4H), 3.62 (br m, 2H), 3.76 (br m, 2H), 6.84 (d, J=9.0 Hz, 1H), 7.46 (d, J=15.3 Hz, 1H), 7.56 (d, J=15.3 Hz, 1H), 7.63 (dd, J=2.7, 8.7 Hz, 1H), 7.83 (d, J=9.0 Hz, 1H), 7.93 (d, J=9.0 Hz, 1H), 7.96 (d, J=2.7 Hz, 1H), 8.70 (br d, 1H). MS (APCI) (M--COO)+ at m/z 466, 468, 470.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[CH:3]=1.[CH3:11][Mg]Br.O>O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH3:11])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C=O
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Br)ccc1C(C)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
To a solution of 4-bromo-2-methylbenzaldehyde (1 g, 5 mmol) in tetrahydrofuran (30 mL) was added methylmagnesium bromide (3N in tetrahydrofuran, 2 mL) at −40° C. Then the mixture was stirred at 25° C. for 3 hours. Water (15 mL) was added to the mixture and then extracted with ethyl acetate (35 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give 1-(4-bromo-2-methylphenyl)ethanol (600 mg, 56%).